CN1898219A - Novel keto-oxadiazole derivatives as cathepsin inhibitors - Google Patents

Novel keto-oxadiazole derivatives as cathepsin inhibitors Download PDF

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CN1898219A
CN1898219A CNA2004800389122A CN200480038912A CN1898219A CN 1898219 A CN1898219 A CN 1898219A CN A2004800389122 A CNA2004800389122 A CN A2004800389122A CN 200480038912 A CN200480038912 A CN 200480038912A CN 1898219 A CN1898219 A CN 1898219A
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alkyl
compound
oxadiazole
morpholine
fluoro
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CN100543017C (en
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S·图赖拉特奈姆
D·J·奥尔德斯
V·勒罗伊
A·P·蒂姆
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Aventis Pharmaceuticals Inc
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Abstract

Novel difluorinated amide derivatives as inhibitors of cathepsin S, K, B, and L, the pharmaceutically acceptable salts and N-oxides thereof, their uses as therapeutic agents and the methods of their making.

Description

New keto-oxadiazole derivatives as cathepsin inhibitors
Invention field
The present invention relates to the purposes of the new keto-oxadiazole derivatives of a class, be used for the treatment of the disease relevant, especially with the active relevant disease of cathepsin S, K and B with L-Cysteine HCL Anhydrous.The invention still further relates to the method for this compounds of preparation.
Background of invention
L-Cysteine HCL Anhydrous has represented that to have cysteine residues on the catalytic site with enzyme be a class peptase of feature.L-Cysteine HCL Anhydrous is relevant with processing with proteic normal degraded.Yet the abnormal activity of L-Cysteine HCL Anhydrous for example, strengthens owing to express to increase or activate, and may cause the pathology consequence.In this respect, some L-Cysteine HCL Anhydrous is relevant with numerous disease, comprises sacroiliitis, atherosclerosis, wind-puff, osteoporosis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, periodontopathy, alochromacy leukodystrophy and other disease.
The active increase of kethepsin such as cathepsin S promotes the pathology and/or the symptom of numerous disease, for example autoimmune disorders includes but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Ge Leifusishi disease, myasthenia gravis, systemic lupus erythematous, intestines irritable, rheumatoid arthritis and struma lymphomatosa; Anaphylactic disease includes but not limited to asthma; And the alloimmunity reaction, include but not limited to organ transplantation or tissue transplantation.Cathepsin S also involves in relating to the relevant disease of excessive elastolysis, as over-drastic air flue elastolysis in chronic obstructive pulmonary disease (for example pulmonary emphysema), bronchiolitis, asthma and the bronchitis, pneumonia and cardiovascular disorder such as plaque rupture (plaque rupture) and atheroma.Cathepsin S relates to fibriilar formation, and therefore, the inhibitor of cathepsin S can be used for treating the general amyloid disease.
For example, the activity of cathepsin B (the F.Mehraban Ann.Rheum.Dis.1997 that in the osteoarthritis model, raises significantly in the synovia; 56,108-115).Similarly, cathepsin K also is a kind of proteolytic enzyme (W.-S.Hou (etc.) Am.J.Pathol.2001 of key in the collagen degradation process of synovia inoblast mediation, 159,2167-2177).Therefore, for example the inhibition of cathepsin B and K is a kind of process useful for the treatment of sex change joint disease such as osteoarthritis.The inhibition of cathepsin K has for example caused inhibition (G.B.Stroup (etc.) the J.Bone Mineral Res.2001 to bone resorption, and 16,1739-1746).Therefore, cathepsin K inhibitor can be used for treating osteoporosis.
Well-known in this area, kethepsin plays an important role in the degradation process of reticular tissue and in the formation of biological activity protein and antigen processing.They relate to osteoporosis, muscular dystrophy, bronchitis, wind-puff, virus infection, cancer metastasis and neurodegenerative disease, and for example chorea pauses Alzheimer's disease and prosperous front yard.Recently, be directed to some potential therapeutic goal, cathepsin inhibitors has been produced increasing interest, for example cathepsin K or cathepsin L are directed to osteoporosis, and cathepsin S is directed to immunomodulatory (W.Kim., K.Kang.Expert Opin.Ther.Pat.2002,12,419-432).The active increase of cathepsin K or B promotes the pathology and/or the symptom of numerous disease.Correspondingly, the molecule of inhibition of histone enzymic activity can be used as this class treatment of diseases agent of treatment.
Summary of the invention
In one aspect of the invention, provide the compound of the enzymic activity of class energy inhibition of histone enzyme S, B and K, it has formula (I) structure:
Figure A20048003891200191
Wherein
A is
Figure A20048003891200201
X 1Be methylene radical, ethylidene or key;
X 2Be CN, CHO, C (O) R 6, C (O) C (O) NR 7R 7, C (O) C (O) NR 7R 8, C (O) C (O) R 13, C (O) C (O) OR 13, C (O) CH 2X 3R 13
X 3Be selected from O, S (O) n, CO, CONH, NHCO, NHSO 2And SO 2NH;
X 4Be CH (R 12) or CH (R 12)-CH 2
X 5Be methylene radical, ethylidene, propylidene or key;
X 6Be key or (C 1-2) alkylene;
R 1Be H, R 13C (O)-, R 13S (O) 2-, R 13OC (O)-, R 8R 7NC (O)-, R 8R 7NS (O) 2-; R 13S (O) 2NC (O)-or R 13C (O) NS (O) 2-; Perhaps R 1Be selected from (C 1-9) alkyl, (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, assorted (C 5-12) cyclic hydrocarbon radical (C 0-6) alkyl, (C 6-12) aryl (C 0-6) alkyl and assorted (C 5-13) aryl (C 0-6) alkyl, each group is replaced by 1 to 5 group that is independently selected from down group alternatively: (C 1-4) alkyl, cyano group, halogen, halo (C 1-4) alkyl ,-X 6NR 9R 9,-X 6OR 9,-X 6SR 9,-X 6C (O) NR 9R 9,-X 6OC (O) NR 9R 9,-X 6C (O) OR 9,-X 6NC (O) OR 9,-X 6S (O) R 10,-X 6S (O) 2R 10And-X 6C (O) R 10
R 2Be selected from hydrogen, (C 1-6) alkyl, (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, assorted (C 5-12) cyclic hydrocarbon radical (C 0-6) alkyl, (C 6-12) aryl (C 0-6) alkyl or assorted (C 5-12) aryl (C 0-6) alkyl;
R 3Be selected from H, (C 1-6) alkyl, (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, assorted (C 5-12) cyclic hydrocarbon radical (C 0-6) alkyl, (C 6-12) aryl (C 0-6) alkyl or assorted (C 5-13) aryl (C 0-6) alkyl, replaced by 1 to 5 group that is independently selected from down group alternatively: (C 1-4) alkyl, cyano group, halogen, halo (C 1-4) alkyl ,-X 6NR 9R 9,-X 6OR 9,-X 6SR 9,-X 6C (O) NR 9R 9,-X 6OC (O) NR 9R 9,-X 6C (O) OR 9,-X 6NC (O) OR 9,-X 6S (O) R 10,-X 6S (O) 2R 10And-X 6C (O) R 10
R 4Be H or (C 1-6) alkyl; Perhaps R 3And R 4With R 3And R 4The carbon atom that both all link to each other forms (C together 3-8) inferior cyclic hydrocarbon radical or (C 3-8) inferior heterocycle alkyl;
R 5Be H, F, or R 5Be (C 1-9) alkyl, (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, assorted (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, (C 6-12) aryl (C 0-6) alkyl, assorted (C 5-13) aryl (C 0-6) alkyl, each group is replaced by 1 to 5 group that is independently selected from down group alternatively: (C 1-4) alkyl, cyano group, halogen, halo (C 1-4) alkyl ,-X 6NR 9R 9,-X 6OR 9,-X 6SR 9,-X 6C (O) NR 9R 9,-X 6OC (O) NR 9R 9,-X 6C (O) OR 9,-X 6NC (O) OR 9,-X 6S (O) R 10,-X 6S (O) 2R 10With-X 6C (O) R 10
R 6Be (C 6-12) aryl, assorted (C 5-13) aryl and halo (C 1-6) alkyl; R wherein 6Replaced by 1 to 5 group that is independently selected from down group alternatively: (C 1-9) alkyl, (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, assorted (C 5-12) cyclic hydrocarbon radical (C 0-6) alkyl, (C 6-12) aryl (C 0-6) alkyl, assorted (C 5-13) aryl (C 0-6) alkyl, cyano group, halogen, halo (C 1-6) alkyl ,-X 6NR 9R 9,-X 6OR 9,-X 6SR 9,-X 6C (O) NR 9R 9,-X 6OC (O) NR 9R 9,-X 6C (O) OR 9,-X 6NC (O) OR 9,-X 6S (O) R 10,-X 6S (O) 2R 10And-X 6C (O) R 10
R 7Be H, (C 1-6) alkyl, (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, assorted (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, (C 6-12) aryl (C 0-6) alkyl, assorted (C 5-13) aryl (C 0-6) alkyl and halo (C 1-6) alkyl; R wherein 7Replaced by 1 to 5 group that is independently selected from down group alternatively: (C 1-4) alkyl, cyano group, halogen, halo (C 1-4) alkyl ,-X 6NR 9R 9,-X 6OR 9,-X 6SR 9,-X 6C (O) NR 9R 9,-X 6OC (O) NR 9R 9,-X 6C (O) OR 9,-X 6NC (O) OR 9,-X 6S (O) R 10,-X 6S (O) 2R 10And-X 6C (O) R 10
R 8Be selected from H, (C 1-6) alkyl, (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, assorted (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, (C 6-12) aryl (C 0-6) alkyl and assorted (C 5-13) aryl (C 0-6) alkyl, or R 7And R 8Form (C with the atom that links to each other 3-8) inferior cyclic hydrocarbon radical or (C 3-8) inferior heterocycle alkyl;
R 9Be hydrogen, (C independently when occurring at every turn 1-6) alkyl or halo (C 1-6) alkyl;
R 10Be (C 1-6) alkyl or halo (C 1-6) alkyl;
R 11Be selected from hydrogen, (C 1-9) alkyl, (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, assorted (C 5-12) cyclic hydrocarbon radical (C 0-6) alkyl, (C 6-12) aryl (C 0-6) alkyl, assorted (C 5-13) aryl (C 0-6) alkyl, (C 9-12) aryl bicyclic (C 0-3) alkyl, assorted (C 8-12)-aryl bicyclic (C 0-3) alkyl ,-C (O) R 13,-C (S) R 13,-S (O) 2R 13,-C (O) OR 13,-C (O) N (R 7) R 8,-C (S) N (R 7) R 8With-S (O) 2N (R 7) R 8
R 12Be H or C 1-6Alkyl, optional by amido, (C 6-12) aryl, assorted (C 5-12) aryl, assorted (C 5-12) cyclic hydrocarbon radical or hydroxyl;
R 13Be (C 1-6) alkyl, (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, assorted (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, (C 6-12) aryl (C 0-6) alkyl, assorted (C 5-13) aryl (C 0-6) alkyl and halo (C 1-6) alkyl; R wherein 13Replaced by 1 to 5 group that is independently selected from down group alternatively: (C 1-4) alkyl, cyano group, halogen, halo (C 1-4) alkyl ,-X 6NR 9R 9,-X 6OR 9,-X 6SR 9,-X 6C (O) NR 9R 9,-X 6OC (O) NR 9R 9,-X 6C (O) OR 9,-X 6NC (O) OR 9,-X 6S (O) R 10,-X 6S (O) 2R 10And-X 6C (O) R 10And
N is zero or integer 1 or 2; And their corresponding N-oxide compounds, their prodrug, their protected derivative, their independent isomer and isomer mixture; And the pharmacy acceptable salt of this class formula (Ia) compound and solvate (for example hydrate) and their N-oxide compound, their prodrug, their protected derivative, their independent isomer and isomer mixture.
In another aspect of this invention, subject matter of an invention is the backbone structure of formula II, III, IV or V, and wherein sub1-sub8 is general substituting group.The concrete substituting group that is positioned at sub1-sub8 is not this part on the one hand of the present invention, but can be substituted any chemical based or group (hereinafter referred to as " general substituting group ") in those positions, comprise that those become possible substituting group by any traditional means or any new technology of exploitation in the future.Therefore, for purposes of this application, " general substituting group " as the component or the restriction claim of claim, and their this may be new for non-obvious or unknown when the present invention produces.
Figure A20048003891200221
Figure A20048003891200231
In another aspect of this invention, the subject matter of an invention general substituting group that comprises the backbone structure of formula II, III, IV or V and be positioned at sub1-sub8.For purposes of this application, " general substituting group " means and making when of the present invention, one of ordinary skill in the art promptly thinks to be applicable to chemical based or the group that replaces in the position of sub1-sub8 by using for reference hereinafter disclosed concrete substituting group, and need not to carry out too much experiment in implementing process of the present invention.
In still another aspect of the invention, subject matter of an invention comprises the backbone structure of formula II, III, IV or V and the hereinafter disclosed concrete substituting group that is positioned at sub1-sub8.The disclosed concrete substituting group of the application is called as " specified substituent ".For purposes of this application, if enumerate a kind of specified substituent in the claims, be as restriction to claim, but and itself or it and backbone structure and other substituent entitle requirement patentability that combines wherein.
Definition:
Unless otherwise specified, the following term that is used for specification sheets and claim part defines for purposes of this application, and has following implication.
" relevant chemical entities " of compound means the N-oxide derivative, prodrug derivatives, protected derivative of described compound, independent isomer, isomer mixture; or pharmacy acceptable salt or solvate, persons skilled in the art need not to carry out too much experiment and can be prepared.
" acyl group " means H-CO-or alkyl-CO-group, and alkyl wherein is as described herein.
" acyl amino " is acyl group-NH-group, and acyl group wherein as defined herein.
"-oxyl " means alkyl-O-group, and alkyl wherein is as described herein.Typical-oxyl comprise allyloxy, difluoro-methoxy, methoxyl group, trifluoromethoxy, oxyethyl group, positive propoxy, isopropoxy, n-butoxy and heptan the oxygen base.
"-oxyl carbonyl " means alkyl-O-CO-group, and alkyl wherein is as described herein.Typical-oxyl carbonyl comprises methoxycarbonyl and ethoxy carbonyl.
" alkyl " itself means straight or branched, saturated or undersaturated aliphatic group, the ((C for example of carbonatoms shown in having 1-6) alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, isobutyl-, the tertiary butyl, vinyl, allyl group, 1-propenyl, pseudoallyl, 1-butylene base, crotyl, 3-butenyl, 2-methacrylic, ethynyl, 1-proyl, 2-propynyl etc.).When alkyl and another group one time-out (for example aryl alkyl) then mean straight or branched, saturated or undersaturated aliphatic divalent group, carbonatoms shown in having, or when atomicity does not mark, then mean key ((C for example 6-12) aryl (C 0-6) alkyl comprises phenyl, benzyl, styroyl, 1-phenylethyl, 3-phenyl propyl etc.).Those skilled in the art person will be understood that when alkyl is represented the unsaturated aliphatic group this class group must not directly be connected with oxygen, nitrogen or sulphur atom by the carbon carbon multiple bond of described unsaturated aliphatic group.
" alkylene " unless point out separately, means straight or branched, saturated or unsaturated aliphatic divalent group, carbonatoms shown in having, (C 1-2) alkylene comprises methylene radical (CH 2-) and ethylidene (CH 2CH 2-).Those skilled in the art person will be understood that when alkylene is represented the unsaturated aliphatic divalent group this class group must not directly be connected with oxygen, nitrogen or sulphur atom by the carbon carbon multiple bond of described unsaturated aliphatic divalent group.
" alkylenedioxy " means-O-alkylene-O-group, and wherein alkylene as defined above.Typical alkylenedioxy comprises methylene radical dioxy base and ethylidene dioxy base.
" alkyl sulfinyl " means alkyl-SO-group, and alkyl wherein is as indicated above.Alkyl in the preferred alkyl sulfinyl is C 1-4Alkyl.
" alkyl alkylsulfonyl " means alkyl-SO 2-group, alkyl wherein is as indicated above.Alkyl in the preferred alkyl alkylsulfonyl is C 1-4Alkyl.
" alkyl sulfenyl " means alkyl-S-group, and alkyl wherein is as indicated above.Typical alkyl sulfenyl comprises methyl sulfenyl, ethyl sulfenyl, sec.-propyl sulfenyl and heptyl sulfenyl.
" aromatic series base " means the group that its composed atom constitutes the unsaturated cyclic system, and all atoms all are that the sum of sp2 hybridized atom and πDian Zi equals 4n+2 in this ring system.
" aroyl " means aryl-CO-group, and aryl wherein is as described herein.Typical aroyl comprises benzoyl and 1-and 2-naphthoyl.
" aroylamino " is aroyl-NH-group, and wherein aroyl as hereinbefore defined.
" aryl " represented: (i) monocycle of 6 of optional replacement to 12 carbon atoms or Ppolynuclear aromatic isocyclic part, for example phenyl or naphthyl as the part of group or group; Or the (ii) fractional saturation Ppolynuclear aromatic isocyclic part of optional replacement, wherein aryl and cyclic hydrocarbon radical or cycloalkenyl group are condensed together to form ring texture, for example tetrahydric naphthalene ring, indenyl or 2,3-hydrindene ring.Unless otherwise defined; aryl can be replaced by one or more aryl substituents; described substituting group can be identical or different, should " aryl substituent " comprise for example acyl group; acyl amino;-oxyl; the-oxyl carbonyl; alkylenedioxy; the alkyl sulfinyl; the alkyl alkylsulfonyl; the alkyl sulfenyl; aroyl; aroylamino; aryl; the aryl-oxyl; aryl-oxyl carbonyl; aryl alkyl sulfenyl; aryloxy; aryloxycarbonyl; aryl sulfonyl kia; aryl sulfonyl; artyl sulfo; carboxyl (or acid bioisostere); cyano group; cyclic hydrocarbon radical; halogen; 4-hetaroylpyrazol; heteroaryl; the heteroaryl-oxyl; heteroaroylamino; heteroaryloxy; the heterocycle alkyl; hydroxyl; nitro; trifluoromethyl;-NY 3Y 4,-CONY 3Y 4,-SO 2NY 3Y 4,-NY 3-C (=O) alkyl ,-NY 3SO 2Alkyl, or alkyl, alternatively by aryl, heteroaryl, hydroxyl or-NY 3Y 4Replace (Y wherein 3And Y 4Be hydrogen, alkyl, aryl, aryl alkyl, cyclic hydrocarbon radical, heteroaryl or heteroaryl alkyl independently; Or-NY 3Y 4Group can form cyclammonium).(the C of typical optional replacement 6-12) aryl includes but not limited to xenyl, bromophenyl, chloro-phenyl-, dichlorophenyl, difluoro-methoxy phenyl, 3,5-dimethylphenyl, ethoxy carbonyl phenyl, fluorophenyl, isopropyl phenyl, p-methoxy-phenyl, aminomethyl phenyl, methyl sulphonyl phenyl, naphthyl, pentafluorophenyl group, phenyl, Trifluoromethoxyphen-l, trifluoromethyl etc.Be used for definition and R as the application 6The substituting group that base connects, (the C of optional replacement 6-12) aryl comprises Trifluoromethoxyphen-l, difluoro-methoxy phenyl, 4-fluorophenyl etc.
" aryl-oxyl " means aryl alkyl-O-group, and aryl alkyl wherein is as indicated above.Typical aryl-oxyl comprises benzyloxy and 1-or 2-naphthalene methoxyl group.
" aryl-oxyl carbonyl " means aryl alkyl-O-CO-group, and aryl alkyl wherein is as indicated above.Typical aryl-oxyl carbonyl is a benzyloxycarbonyl.
" aryl alkyl sulfenyl " means aryl alkyl-S-group, and aryl alkyl wherein is as indicated above.Typical aryl alkyl sulfenyl is the benzyl sulfenyl.
" aryloxy " means aryl-O-group, and aryl wherein is as indicated above.Typical aryloxy comprises phenoxy group and naphthyloxy, is substituted alternatively separately.
" aryloxycarbonyl " mean aryl-O-C (=O)-group, aryl wherein is as indicated above.Typical aryloxycarbonyl comprises phenyloxycarbonyl and naphthyloxy carbonyl.
" aryl sulfonyl kia " means aryl-SO-group, and aryl wherein is as indicated above.
" aryl sulfonyl " means aryl-SO 2-group, aryl wherein is as indicated above.
" artyl sulfo " means aryl-S-group, and aryl wherein is as indicated above.Typical artyl sulfo comprises phenyl sulfenyl and naphthyl sulfenyl.
" cyclic hydrocarbon radical " means saturated or part is unsaturated, contain shown in monocycle, condensed-bicyclic or the bridging of ring carbon atom number encircle combination, and any carbocyclic ring ketone, thioketones or imino-ketone derivatives ((C for example more 3-12) cyclic hydrocarbon radical comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, two ring [2.2.2] octyl groups, diamantane-1-base, decahydro naphthyl, oxo cyclohexyl, dioxo cyclohexyl, sulfo-cyclohexyl, 2-oxo two rings [2.2.1] heptan-1-base or the like).Those skilled in the art person will be understood that this class ring must not directly be connected with oxygen, nitrogen or sulphur atom by carbon carbon multiple bond when cyclic hydrocarbon radical is represented the unsaturated cyclic combination.
" inferior cyclic hydrocarbon radical " mean the saturated or part of two valencys unsaturated, contain shown in the monocycle or the bridging of ring carbon atom number encircle combination, and any carbocyclic ring ketone, thioketones or imino-ketone derivatives more.
" 4-hetaroylpyrazol " mean heteroaryl-C (=O)-group, heteroaryl wherein is as described herein.Typical heteroaryl comprises the pyridyl carbonyl.
" heteroaroylamino " means 4-hetaroylpyrazol-NH-group, and heteroaryl wherein is as indicated above.
" heteroaryl " is as the part of group or group, expression: (i) optional replacement has about 5 to the aromatic series monocycle of about 13 annular atomses or encircle organic moiety more, wherein one or more annular atomses are the elements beyond the carbon, nitrogen for example, (this class examples of groups comprises benzimidazolyl-benzoxazolyl for oxygen or sulphur, benzothiazolyl, furyl, imidazolyl, indyl, indolizine base isoxazolyl, isoquinolyl, isothiazolyl oxadiazole base oxazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrryl, quinazolyl, quinolyl, 1,3, the 4-thiadiazolyl group, thiazolyl, thienyl and triazolyl, replaced by one or more aryl substituents as defined above alternatively, unless otherwise defined); The (ii) assorted isocyclic part of many rings of the fractional saturation of optional replacement, wherein heteroaryl and cyclic hydrocarbon radical or cycloalkenyl group condense and form ring texture together (this class examples of groups comprises the pyrindane base, replaced by one or more " aryl substituent " as defined above alternatively, unless otherwise defined).Optionally substituting group comprises one or more " aryl substituents " as defined above, unless otherwise defined.Be used to define R as the application 6Used substituting group, the assorted (C of optional replacement 5-13) aryl comprises benzoxazole-2-base, the 5-tertiary butyl-[1,2,4] oxadiazole-3-base, 3-cyclopropyl-1,2,4-oxadiazole-5-base, 5-cyclopropyl-1,2,4-oxadiazole-5-base, 5-cyclopropyl-1,3,4-oxadiazole-2-base, 5-ethyl-[1,3,4] oxadiazole-2-bases, 5-(4-fluoro-phenyl)-1,2,4-oxadiazole-3-base, 5-Yi propyl group isoxazole-3-base, 5-(5-methyl-isoxazole-3-yl)-oxazoles-2-base oxazole-2-base, 3-phenyl-1,2,4-oxadiazole-5-base, 5-phenyl-1,2,4-oxadiazole-3-base, 3-(tetrahydrochysene-pyrans-4-yl)-1,2,4-oxadiazole-5-base, 5-thiophene-2-Ji oxazole-2-base, 5-(4-Trifluoromethoxyphen-l)-1,3,4-oxadiazole-2-base etc.
" heteroaryl-oxyl " means heteroaryl alkyl-O-group, and heteroaryl alkyl wherein is as indicated above.Typical heteroaryloxy comprises the pyridyl methoxyl group of optional replacement.
" heteroaryloxy " means heteroaryl-O-group, and heteroaryl wherein is as indicated above.Typical heteroaryloxy comprises the pyridyloxy of optional replacement.
" heterocycle alkyl " means cyclic hydrocarbon radical as defined in this Application, but one or more ring carbon atom shown in it be selected from-N=,-NR-,-O-or-heteroatom moiety of S-replaces, wherein R is hydrogen, (C 1-6) alkyl, protecting group or represent as with the free valency of theheterocyclic nitrogen atom tie point, and any carbocyclic ring ketone, thioketones or the imino-ketone derivatives (assorted (C of term for example 5-12) cyclic hydrocarbon radical comprises imidazolidyl, morpholinyl, piperazinyl, piperidyl, pyrrolidyl, pyrrolinyl, quinuclidinyl etc.).The protecting group that is fit to comprises tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxy-benzyl, 2-nitrobenzyl etc.Not protected derivative and protected derivative all belong to scope of the present invention.
" inferior heterocycle alkyl " means inferior cyclic hydrocarbon radical as defined in this Application, but shown one or more ring carbon atoms be selected from-N=,-NR-,-O-,-S-or-S (O) 2-heteroatom moiety replace, wherein R is hydrogen, (C 1-6) alkyl or protecting group.
Employed in the disclosure " isomer " mean have identical molecular formula but wherein the essence of atom or atoms in space different with binding sequence arrange different compounds of the present invention.The isomer that the atom spatial disposition is different is called as " steric isomer ".Mutually not each other the steric isomer of mirror image be called as " diastereomer ", the steric isomer that its mirror image can not overlap each other then is called as " enantiomer " or is called as " optical isomer " sometimes.The carbon atom that is connected with four mutually different substituting groups is called as " chiral centre ".Compound with a chiral centre has two kinds of enantiomeric forms that chirality is opposite." racemic mixture " contains two kinds of enantiomers simultaneously, and its ratio is 1: 1.But, with regard to the application, when two kinds of enantiomers exist simultaneously,, all adopt racemic mixture then regardless of the ratio between them.Compound with an above chiral centre has 2 N-1Enantiomorph is right, and wherein n is the number of chiral centre.Compound with an above chiral centre can exist with the form of independent diastereomer, or, is called " diastereo-isomerism mixture " as non-enantiomer mixture.When having a chiral centre, steric isomer can characterize with the absolute configuration of this chiral centre.Absolute configuration is meant the substituent spatial disposition that links to each other with chiral centre.Enantiomer characterizes with the absolute configuration of their chiral centres, and is illustrated according to R-and the S-Cahn-Ingold-Prelog sequence rule that Cahn, Ingold and Prelog proposed.The convention of stereochemistry name, determine the method for stereochemical structure and the method for separation of stereoisomers, in the present technique field be well-known (for example consult " Advanced Organic Chemistry ", the 4th edition, March, Jerry, John Wiley ﹠amp; Sons, NewYork, 1992).Should be appreciated that, be used to describe the title of The compounds of this invention and illustration in the disclosure and mean and comprise all possible steric isomer.Therefore; for example; morpholine-4-formic acid { 1-[1-(3-cyclopropyl-[1; 2; 4] oxadiazole-5-carbonyl)-and the propyl group formamyl]-3; 3-difluoro hexyl }-this title of acid amides mean comprise morpholine-4-formic acid (S)-1-[(S)-1-(3-cyclopropyl-1; 2; 4-oxadiazole-5-carbonyl)-and the propyl group formamyl]-3; 3-difluoro hexyl }-acid amides and morpholine-4-formic acid (R)-1-[(R)-and 1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3; 3-difluoro hexyl }-acid amides and any mixture thereof, racemize or other type.
The nitrogen that " N-oxide derivative " means wherein is in the derivative of the The compounds of this invention of the state of oxidation (being N-O), and has required pharmacological activity.
" pharmaceutically acceptable " means it and can be used for pharmaceutical compositions, this pharmaceutical composition is normally safe, atoxic, and biologically or others all do not have negative influence, and all be acceptable aspect veterinary science purposes and the human medicinal use.
" pharmacy acceptable salt " means the salt of The compounds of this invention, and they are pharmaceutically acceptable as defined above, and has required pharmacological activity.This class salt comprises and the mineral acid example hydrochloric acid; Hydrogen bromide; sulfuric acid; nitric acid; phosphoric acid etc. or the acid salt that forms with following organic acid: acetate; propionic acid; caproic acid; enanthic acid; cyclopentyl propionic acid; oxyacetic acid; pyruvic acid; lactic acid; propanedioic acid; succsinic acid; oxysuccinic acid; toxilic acid; fumaric acid; tartrate; citric acid; phenylformic acid; neighbour-(4-hydroxy benzoyl) phenylformic acid; styracin; amygdalic acid; methylsulphonic acid; ethyl sulfonic acid; 1; the 2-ethionic acid; the 2-ethylenehydrinsulfonic acid; Phenylsulfonic acid; p-chlorobenzenesulfonic acid; the 2-naphthene sulfonic acid; tosic acid; camphorsulfonic acid; 4-methyl bicyclic [2.2.2] oct-2-ene-1-formic acid; glucoheptonic acid; 4,4 '-methylene-bis (3-hydroxyl-2-alkene-1-formic acid); the 3-phenylpropionic acid; trimethylacetic acid; tert.-butylacetic acid; bay sulfuric acid; glyconic acid; L-glutamic acid; hydroxynaphthoic acid; Whitfield's ointment; stearic acid; muconic acid etc.
Pharmacy acceptable salt comprises that also the acid proton when existence can react and the base addition salt of formation with mineral alkali or organic bases.Acceptable mineral alkali comprises sodium hydroxide, yellow soda ash, potassium hydroxide, aluminium hydroxide and calcium hydroxide.Acceptable organic bases comprises thanomin, diethanolamine, trolamine, tromethane, N-methylglucosamine etc.
" prodrug " means the compound that can be converted into The compounds of this invention in vivo through metabolism.The ester that for example contains the The compounds of this invention of hydroxyl can be converted into parent molecule through hydrolysis in vivo.Equally, the ester that contains the The compounds of this invention of carboxyl can be converted into parent molecule through hydrolysis in vivo.The suitable ester that contains the The compounds of this invention of hydroxyl has for example acetic ester, citrate, lactate, tartrate, malonic ester, barkite, salicylate, propionic ester, succinate, fumarate, maleic acid ester, methylene radical-two-b-hydroxynaphthoic acid ester, rough gentian acid esters, isethionic acid ester, two toluoyl tartrates, methanesulfonate ester, esilate, benzene sulfonate, p-toluenesulfonic esters, cyclohexyl sulfamate and quinate.The suitable ester that contains the The compounds of this invention of carboxyl for example has F.J.Leinweber at Drug Metab.Res., those esters described in 1987,18,379 pages.The particularly useful ester of a class that contains the The compounds of this invention of hydroxyl can be from being selected from Bundgaard etc. at J.Med.Chem., 1989,32, those acid preparations described in the 2503-2507, they comprise the amino methyl benzoic ether of replacement, dialkyl amino methyl benzoic ether for example, wherein two alkyl can link together and/or be separated with the nitrogen-atoms of Sauerstoffatom or optional replacement, hydrocarbylation nitrogen-atoms for example, especially morpholine methyl benzoic ether, for example 3-or 4-(morpholine methyl)-benzoic ether, and (4-alkyl piperazine-1-yl) benzoic ether, for example 3-or 4-(4-alkyl piperazine-1-yl) benzoic ether.
" protected derivative " means the derivative of the The compounds of this invention of the protected base sealing of wherein one or more reaction site.The protected derivative of The compounds of this invention can be used for preparing The compounds of this invention, or itself also can be effective cathepsin S inhibitor.About the catalogue of more complete due care base, can consult " blocking group in the organic synthesis " (T.W.Greene, the 3rd edition, John Wiley ﹠amp; Sons, Inc., 1999).
" treatment significant quantity " means when being applied to certain animal when treating certain disease, is enough to make this treatment this disease to be produced the dosage of curative effect.
" treatment " means any of The compounds of this invention and uses, and comprising:
(1) may easily suffer from this disease but not experience as yet or manifest that preventing disease takes place in the animal of this disease pathology or symptom,
(2) suppress disease (promptly stoping further developing of this pathology and/or symptom) just experiencing or manifest in the animal of this disease pathology or symptom, or
(3) make in the animal of this disease pathology or symptom that sb.'s illness took a favorable turn (promptly reversing this pathology and/or symptom) just experiencing or manifest.
Name:
The compounds of this invention and be used for the intermediate of its preparation and raw material according to the name of IUPAC rule, characteristic group wherein is as follows as the priority ranking that successively decreases of main base: acid, ester, acid amides etc.Perhaps, this compound is according to AutoNom 4.0 softwares (Beilstein Information Systems, Inc.) name.[for example, formula (I) compound, wherein R 1Be morpholine-4-carbonyl, X 1Be methylene radical, R 5Be methyl, R 2Be that H and A are
Figure A20048003891200301
R wherein 3Be ethyl, R 4Be H and X 2Be C (O) R 6, R wherein 6Be 3-cyclopropyl-1,2,4-oxadiazole-5-base; The compound that promptly has following structure:
Be named as morpholine-4-formic acid (S)-1-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-difluoro butyl }-acid amides.
Yet, should be appreciated that, for a certain particular compound of mentioning with structural formula and name simultaneously,, be as the criterion with structural formula if structural formula and name are internally inconsistent.
Various characteristics as its novelty of feature of the present invention will particularly point out in claim appended and that constitute a disclosure part.For more profoundly understand the present invention, it the enforcement advantage and rise to use the specific purpose that is reached, should be with reference to following explanation, its illustrated and narrated this
The preferred embodiment of invention.
The detailed description of preferred implementation
About the compound of above-mentioned formula (I), below be concrete several classes:
X 1Can represent methylene radical especially.
A can represent especially Wherein: R 3Be H, (C 6-12) aryl (C 2-6) alkyl or alternatively by-X 6OR 9(C 1-6) alkyl [X wherein 6Be key and R 9Be (C 1-6) alkyl]; R 4Be H or (C 1-6) alkyl; X 2Be CHO, CN or C (O) R 6[R wherein 6Be alternatively by (C 1-9) alkyl, (C 3-12) cyclic hydrocarbon radical, (C 6-12) aryl or assorted (C 5-13) assorted (C of aryl 5-13) aryl].
A also can represent especially
Figure A20048003891200312
X wherein 5Be propylidene and R 11Be-C (O) OR 13Or-S (O) 2R 13, R wherein 13Be alkyl or (C 6-12) aryl.
R 1Can represent R especially 13C (O)-, R wherein 13Be assorted (C 5-12) cyclic hydrocarbon radical.
R 1Also can represent R especially 13OC (O)-, R wherein 13Be (C 6-12) aryl (C 1-6) alkyl.
R 1Also can represent (C especially 1-9) alkyl.
R 1Also can represent assorted (C especially 5-12) cyclic hydrocarbon radical.
R 2Can represent H especially.
R 5Can represent (C especially 1-9) alkyl.
R 5Also can represent (C especially 6-12) aryl (C 1-6) alkyl.
Special kind:
One group of special The compounds of this invention is the compound of formula (Ia):
Figure A20048003891200321
R wherein 1, R 3, R 4And R 5As mentioned above, and their corresponding N-oxide compounds, their prodrug, their protected derivative, their independent isomer and isomer mixture; And the pharmacy acceptable salt and the solvate (for example hydrate) of this class formula (Ia) compound and their N-oxide compound, their prodrug, their protected derivative, their independent isomer and isomer mixture.
Example has formula (Ia) compound, wherein R 1Be R 13C (O)-and R 13Be assorted (C 5-12) cyclic hydrocarbon radical.Special example has formula (Ia) compound, wherein R 1Be
Example has formula (Ia) compound, wherein R 3Be H, (C 6-12) aryl (C 1-6) alkyl or (C 1-6) alkyl.Special example has formula (Ia) compound, wherein R 3Be H, Or CH 3-CH 2-CH 2-.
Example has wherein R 4It is formula (Ia) compound of H or methyl.
Example has wherein R 5Be (C 6-12) aryl (C 1-6) formula (Ia) compound of alkyl.
Special example has wherein R 5Representative Formula (Ia) compound.
One group of special The compounds of this invention is the compound of formula (Ia), wherein: R 1Be R 13C (O)-(especially
Figure A20048003891200332
R 3Be H, (C 6-12) aryl (C 1-6) alkyl (especially Or (C 1-6) alkyl (CH especially 3-CH 2-CH 2-); R 4Be H or methyl and R 5Be (C 6-12) aryl (C 1-6) alkyl (especially
Figure A20048003891200334
One group of special The compounds of this invention is the compound of formula (Ib), wherein: R 1Be R 13C (O)-(especially
Figure A20048003891200335
R 3Be H, (C 6-12) aryl (C 1-6) alkyl (especially
Figure A20048003891200336
Or (C 1-6) alkyl (CH especially 3-CH 2-); R 4Be H or methyl and R 5Be (C 6-12) aryl (C 1-6) alkyl (especially
Another organizes the compound that special The compounds of this invention is formula (Ic):
R wherein 1, R 3, R 4, R 5And R 6Be as mentioned above, and their corresponding N-oxide compounds, their prodrug, their protected derivative, their independent isomer and isomer mixture; And the pharmacy acceptable salt and the solvate (for example hydrate) of this class formula (Ic) compound and their N-oxide compound, their prodrug, their protected derivative, their independent isomer and isomer mixture.
Example has formula (Ic) compound, wherein R 1Be R 13C (O)-and R 13Be assorted (C 5-12) cyclic hydrocarbon radical.Special example has formula (Ic) compound, wherein R 1Be
Example has formula (Ic) compound, wherein R 3Be alternatively by-X 6OR 9[X wherein 6Be key and R 9Be (C 1-6) alkyl] (the C that replaces 1-6) alkyl.Special example has formula (Ic) compound, wherein R 3Be CH 3-CH 2-, CH 3-CH 2-CH 2-or CH 3-O-CH 2-.
Example has wherein R 4Be the formula (Ic) and the compound of H or methyl.Example has wherein R 4It is formula (Ic) compound of H.
Example has formula (Ic) compound, wherein R 5Be (C 1-9) alkyl or (C 6-12) aryl (C 1-6) alkyl.Special example has formula (Ic) compound, wherein R 5Represent CH 3CH 2CH 2Or CH 3CH 2Or CH 3Or
Figure A20048003891200342
Special example has wherein R 5Representative
Figure A20048003891200343
Formula (Ic) compound.
Example has formula (Ic) compound, wherein R 6Be assorted (C 5-13) aryl, alternatively by (C 1-9) alkyl, (C 3-12) cyclic hydrocarbon radical, (C 6-12) aryl or assorted (C 5-13) the aryl replacement.Assorted (the C of typical optional replacement 5-13) aryl comprises the benzoxazolyl, oxadiazole base, isoxazolyl Huo oxazolyl of optional replacement.Example has formula (Ic) compound, wherein R 6It is benzoxazole-2-base, the 5-tertiary butyl-[1,2,4] oxadiazole-3-base, 3-cyclopropyl-1,2,4-oxadiazole-5-base, 5-cyclopropyl-1,2,4-oxadiazole-2-base, 5-cyclopropyl-1,3,4-oxadiazole-2-base, 5-ethyl-1,3,4-oxadiazole-2-base, 5-(4-fluoro-phenyl)-1,2,4-oxadiazole-3-base, 5-Yi propyl group isoxazole-3-base, 5-(5-methyl-isoxazole-3-yl)-oxazoles-2-base, 5-(5-thiotolene-2-yl)-oxazoles-2-base oxazole-2-base, 3-phenyl-1,2,4-oxadiazole-5-base, 5-phenyl-1,2,4-oxadiazole-3-base, 5-thiophene-2-Ji oxazole-2-base, 5-(4-Trifluoromethoxyphen-l)-1,3,4-oxadiazole-2-base etc.Wherein R6 is benzoxazole-2-base, 3-cyclopropyl-1,2, and formula (Ic) compound of 4-oxadiazole-5-Ji, oxazole-2-base is special example.
One group of special The compounds of this invention is the compound of formula (Ic), wherein: R 1Be R 13C (O)-(especially
Figure A20048003891200351
R 3Be alternatively by X 6OR 9-(CH especially 3-CH 2-, CH 3-CH 2-CH 2-or CH 3-O-CH 2-) (C that replaces 1-6) alkyl; R 4Be H and R 5Be (C 1-9) alkyl or (C 6-12) aryl (C 1-6) alkyl (especially R 6Be assorted (C 5-13) aryl, alternatively by (C 1-9) alkyl, (C 3-12) cyclic hydrocarbon radical, assorted (C 5-12) cyclic hydrocarbon radical, (C 6-12) aryl or assorted (C 5-13) aryl (especially benzoxazole-2-base, 3-cyclopropyl-1,2,4-oxadiazole-5-Ji, oxazole-2-base and 5-methyl-isoxazole-3-Ji oxazole-2-yl) replaces.
Another organizes the compound that special The compounds of this invention is formula (Id):
Figure A20048003891200353
R wherein 1, R 5, R 11And X 5As mentioned above, and their corresponding N-oxide compounds, their prodrug, their protected derivative, their independent isomer and isomer mixture; And this class formula (Id) compound and their N-oxide compound, their prodrug, their protected derivative, and the pharmacy acceptable salt of their independent isomer and isomer mixture and solvate (for example hydrate).
Example has formula (Id) compound, wherein R 1Be R 13C (O)-and R 13Be assorted (C 5-12) cyclic hydrocarbon radical.Special example has formula (Id) compound, wherein R 1Be
Example has formula (Id) compound, wherein R 5Be (C 6-12) aryl (C 1-6) alkyl.Special example has formula (Id) compound, wherein R 5Representative
Figure A20048003891200361
Example has formula (Id) compound, wherein R 11Be-C (O) OR 13Or-S (O) 2R 13, R wherein 13Be alkyl or (C 6-12) aryl.Special example has formula (Id) compound, wherein R 11Representative-C (O) OC (CH 3) 3Or
Figure A20048003891200362
Example has wherein X 1It is formula (Id) compound of propylidene.
One group of special The compounds of this invention is formula (Id) compound, wherein R 1Be R 13C (O)-(especially
Figure A20048003891200363
R 5Be (C 6-12) aryl (C 1-6) alkyl (especially R 11Be-C (O) OR 13[especially-C (O) OC (CH 3) 3] or-S (O) 2R 13(especially And X 1It is propylidene.
Special The compounds of this invention comprises:
Morpholine-4-formic acid (S)-1-[(S)-and 1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides;
Morpholine-4-formic acid (S)-1-[(S)-and 1-(5-cyclopropyl-1,3,4-oxadiazole-2-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides;
Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{ (S)-1-[5-(4-Trifluoromethoxyphen-l)-1,3,4-oxadiazole-2-carbonyl]-the propyl group formamyl }-hexyl)-acid amides;
Morpholine-4-formic acid (S)-1-[(S)-and 1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-two fluoro-4-phenyl-butyl }-acid amides;
Morpholine-4-formic acid 1-[1-(3-cyclopropyl-[1,2,4] oxadiazole-5-carbonyl)-propyl group formamyl] and-3,3-two fluoro-5-methyl-hexyls }-acid amides;
Morpholine-4-formic acid (S)-1-[(S)-and 1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-difluoro butyl }-acid amides;
Morpholine-4-formic acid (S)-3,3-two fluoro-1-[(S)-1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-butyl }-acid amides;
Morpholine-4-formic acid (S)-3,3-two fluoro-1-[(S)-1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl group formamyl]-butyl }-acid amides;
Morpholine-4-formic acid 1-[1-(5-cyclopropyl-[1,3,4] oxadiazole-2-carbonyl)-propyl group formamyl] and-3,3-two fluoro-4-phenyl-butyl }-acid amides;
Morpholine-4-formic acid 3,3-two fluoro-1-[1-(the different propyl group isoxazole of 5--3-carbonyl)-propyl group formamyl]-hexyl }-acid amides;
Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{1-[5-(5-methyl-isoxazole-3-yl)-oxazole-2-carbonyl]-the propyl group formamyl }-hexyl)-acid amides;
Morpholine-4-formic acid (S)-3,3-two fluoro-1-[(S)-1-(oxazole-2-carbonyl)-propyl group formamyl]-4-phenyl-butyl }-acid amides;
Morpholine-4-formic acid (S)-3,3-two fluoro-4-phenyl-1-[(S)-1-(5-thiophene-2-base oxazole-2-carbonyl)-propyl group formamyl]-butyl }-acid amides;
Morpholine-4-formic acid (S)-1-[(S)-and 1-(benzoxazole-2-carbonyl)-butyl formamyl]-3,3-two fluoro-4-phenyl-butyl }-acid amides;
Morpholine-4-formic acid [1-(2-benzoxazole-2-base-1-methoxymethyl-2-oxoethyl formamyl)-3,3-two fluoro-4-phenyl-butyl]-acid amides;
Morpholine-4-formic acid (S)-1-[(S)-and 1-(benzoxazole-2-carbonyl)-1-methyl-butyl formamyl]-3,3-two fluoro-4-phenyl-butyl }-acid amides;
Morpholine-4-formic acid [(S)-and 1-((S)-1-cyano group-3-phenyl propyl formamyl)-3,3-two fluoro-4-phenyl-butyl]-acid amides;
Morpholine-4-formic acid [(S)-and 1-(cyano methyl-formamyl)-3,3-two fluoro-4-phenyl-butyl]-acid amides;
Morpholine-4-formic acid [(S)-3,3-two fluoro-1-((S)-1-formyl radical-1-methyl-butyl formamyl)-4-phenyl-butyl]-acid amides;
Morpholine-4-formic acid (S)-and 1-[1-(5-ethyl-[1,3,4] oxadiazole-2-carbonyl)-propyl group formamyl]-3,3-two fluoro-4-phenyl-butyl }-acid amides;
Morpholine-4-formic acid (S)-and 1-[1-(the 5-tertiary butyl-[1,2,4] oxadiazole-3-carbonyl)-propyl group formamyl]-3,3-two fluoro-4-phenyl-butyl }-acid amides;
Morpholine-4-formic acid (S)-3,3-two fluoro-4-phenyl-1-[(S)-1-(5-phenyl-[1,2,4] oxadiazole-3-yl)-propyl group formamyl]-butyl }-acid amides;
[(S)-and 1-(cyano methyl-formamyl)-3,3-two fluoro-4-phenyl-butyl]-benzyl carbamate;
(S)-4,4-two fluoro-5-phenyl-2-(tetrahydrochysene-pyrans-4-base is amino)-valeric acid Cyanomethyl amides;
(S)-4,4-two fluoro-2-isobutylamino-5-phenylpentanoic acid Cyanomethyl amides;
Morpholine-4-formic acid [(S)-and 1-((S)-1-benzenesulfonyl-3-oxo-azepan-4-base formamyl)-3,3-two fluoro-4-phenyl-butyl]-acid amides;
(S)-and 4-{ (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls)-amino]-5-phenyl pentanoyl amino }-3-oxo-azepan-1-t-butyl formate;
Morpholine-4-formic acid ((S)-1-{ (S)-1-[(5-ethyl-1,3,4-oxadiazole-2-yl)-hydroxymethyl]-the propyl group formamyl }-3,3-difluoro hexyl)-acid amides;
Morpholine-4-formic acid (S)-and 1-[1-(5-cyclopropyl-1,3,4-oxadiazole-2-carbonyl)-propyl group formamyl]-3,3-difluoro butyl }-acid amides;
Morpholine-4-formic acid (S)-and 1-[1-(5-cyclopropyl-1,2,4-oxadiazole-3-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides;
Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{ (S)-1-[5-(4-fluoro-phenyl)-1,2,4-oxadiazole-3-carbonyl]-the propyl group formamyl }-butyl)-acid amides;
Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{1-[5-(4-fluoro-phenyl)-1,2,4-oxadiazole-3-carbonyl]-the propyl group formamyl }-butyl)-acid amides;
Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{ (R)-1-[5-(4-fluoro-phenyl)-1,2,4-oxadiazole-3-carbonyl]-the propyl group formamyl }-butyl)-acid amides;
Morpholine-4-formic acid (S)-1-[(S)-1-(benzoxazole-2-carbonyl)-the propyl group formamyl]-3,3-difluoro butyl }-acid amides;
Morpholine-4-formic acid [(S)-and 1-(cyano methyl-formamyl)-3,3-difluoro hexyl]-acid amides;
Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{ (R)-1-[5-(5-thiotolene-2-yl)-oxazole-2-carbonyl]-the propyl group formamyl }-hexyl)-acid amides;
Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{ (S)-1-[5-(5-thiotolene-2-yl)-oxazole-2-carbonyl]-the propyl group formamyl }-hexyl)-acid amides;
And their corresponding N-oxide compounds, their prodrug, their protected derivative, their independent isomer and isomer mixture; And the pharmacy acceptable salt and the solvate (for example hydrate) of this class formula (Ia) compound and their N-oxide compound, their prodrug, their protected derivative, their independent isomer and isomer mixture.
Pharmacology and purposes:
The compounds of this invention is the inhibitor of cathepsin S, therefore can be used for treating the wherein active pathology of disease and/or the disease of symptom of promoting of cathepsin S.For example, The compounds of this invention can be used for treating autoimmune disorders, includes but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Ge Leifusishi disease, myasthenia gravis, systemic lupus erythematous, intestines irritable, rheumatoid arthritis and struma lymphomatosa; Anaphylactic disease includes but not limited to asthma; And the alloimmunity reaction, include but not limited to organ transplantation or tissue transplantation.
Cathepsin S also involves in the disease that relates to excessive elastolysis, as the excessive air flue elastolysis in chronic obstructive pulmonary disease (for example pulmonary emphysema), bronchiolitis, asthma and the bronchitis, pneumonia, and cardiovascular disorder are as plaque rupture and atheroma.Cathepsin S involves in fibriilar formation, and therefore, the inhibitor of cathepsin S can be used for treating the general amyloidosis.
The L-Cysteine HCL Anhydrous of The compounds of this invention suppresses active and can measure by the method known to persons skilled in the art.Being used to measure tissue protein enzymic activity and test compound is known to the suitable in vitro tests method of its inhibition.Usually, this test method(s) is measured the hydrolysis of proteolytic enzyme inductive peptide substrate.The test details of measuring protease inhibiting activity describes in detail among the embodiment 31,32,33 and 34 hereinafter.
The compounds of this invention also is the inhibitor of cathepsin K and B, therefore can be used for treating wherein cathepsin K and the active pathology of disease and/or the disease of symptom of promoting of B.For example, The compounds of this invention can be used for treating pain, osteoarthritis, osteoporosis or cancer, as lung cancer, leukemia (B-and T-cell, acute), ovarian cancer, sarcoma, Kaposi sarcoma, intestinal cancer, lymphoglandula cancer, brain tumor, mammary cancer, carcinoma of the pancreas, prostate cancer or skin carcinoma.
Administration and pharmaceutical composition:
Usually, The compounds of this invention will via known in the art any utilize with acceptable manner with the administration of treatment significant quantity, individually dosed or with one or more therapeutical agent Combined Preparation.The effectiveness and other factor that depend on severity, patient's age and relative healthy state, the compound used therefor of disease, significant quantity can great changes have taken place in treatment.For example, the treatment significant quantity of The compounds of this invention can about 1 microgram/per kilogram of body weight (μ g/kg) be to about 60 milligrams/per kilogram of body weight every day (mg/kg) from every day, and common about 1 μ g/kg/ day is about 20mg/kg/ day extremely.Therefore, for the patient of 80kg, the treatment significant quantity can be from about 80 μ g/ days to about 4.8g/ day, usually from about 80 μ g/ days to about 1.6g/ day.Usually, the one of ordinary skilled in the art relies on he or she's knowledge and of the present invention open, can determine to treat the treatment significant quantity of the The compounds of this invention of certain disease specific.
The compounds of this invention can be with the form of pharmaceutical composition by following a kind of administration: oral, whole body (for example in skin, nose or with the form of suppository) or parenteral (for example intramuscular, intravenously or subcutaneous).The form of pharmaceutical composition can be tablet, pill, capsule, semisolid, powder, sustained release dosage, solution, suspension, elixir, aerosol or any other suitable composition, and usually by forming with the The compounds of this invention of at least a pharmaceutically acceptable excipient composition.Acceptable vehicle be atoxic, be convenient to administration, and can not produce adverse influence to the treatment benefit of activeconstituents.This class vehicle can be any solid, liquid, semisolid, or under the situation of aerosol combination, can be the gas vehicle that those skilled in the art obtain usually easily.
The solid pharmaceutical vehicle comprises starch, Mierocrystalline cellulose, talcum, glucose, lactose, sucrose, gelatin, Fructus Hordei Germinatus, rice, flour, chalk, silica gel, Magnesium Stearate, sodium stearate, Zerol, sodium-chlor, exsiccant skimming milk etc.Liquid and semisolid excipient can be selected from water, ethanol, glycerine, propylene glycol and various oil, comprise the oil (for example peanut oil, soya-bean oil, mineral oil, sesame wet goods) in those oil, animal, plant or synthetic source.Preferably the liquid vehicle in particular for injection liquid comprises water, salt solution, D/W and glycol.
Depend on the type of preparation, the size of unitary dose, the other factors known to the kind of vehicle and the medical science field skilled person, the amount in composition can great changes have taken place for The compounds of this invention.Usually, the composition of the The compounds of this invention of treatment specified disease can contain the activeconstituents of 0.01%w to 10%w, preferred 0.3%w to 1%w, and all the other are one or more vehicle.Preferably, pharmaceutical composition is administered for continuous treatment with single unit dosage form, maybe when the special mitigation symptoms of needs arbitrarily with single unit dosage form administration.The representative drugs preparation that contains The compounds of this invention has been described in embodiment 35.
Chemistry:
The method for preparing The compounds of this invention:
The compounds of this invention can prepare by adopting and revising known method, so-called known method be meant used already so far or document described in method, for example R.C.Larock is in those methods described in " organic conversion complete works " (VCH publishers, 1989).
In the various reactions of the following stated, when needing some reactive functional group in final product, for example hydroxyl, amino, imino-, sulfenyl or carboxyl have and must protect them, in case they undesirably participate in reaction.Traditional protecting group can be used according to standing procedure, for example, can consult " protecting group in the organic chemistry " (JohnWiley and Sons, 1991) of T.W.Greene and P.G.M.Wuts.
Compound of the present invention can be prepared according to reaction synoptic diagram 1:
Reaction synoptic diagram 1
Figure A20048003891200421
X wherein 1, R 1, R 3, R 4, R 5And R 6Define during respectively the present invention summarizes freely.Therefore, in step 1, acid can with the aminocompound condensation shown in the general formula, to produce the beta-hydroxy acid amides.This condensation reaction can be carried out in envrionment temperature, adopts suitable coupling agent (benzotriazole-1-base oxygen base tripyrrole Wan Ji Phosphonium hexafluorophosphate (PyBOP for example ), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI), O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HBTU), 1,3-dicyclohexylcarbodiimide (DCC) etc.), and randomly adopt suitable catalyzer (I-hydroxybenzotriazole (HOBt) for example, 1-hydroxyl-7-azepine benzotriazole (HOAt), O-(7-azepine benzo triazol-1-yl)-1,1,3,3-tetramethyl-urea hexafluorophosphate (HATU) etc.) and non-nucleophilicity alkali (triethylamine for example, N-methylmorpholine etc. or its any suitable combination), needed finish in 2 to 10 hours.Then, this beta-hydroxy acid amides can oxidation in step 2, production (Ic) compound.This oxidizing reaction can adopt DMP (Dess-Martin periodinane) in inert solvent such as methylene dichloride, carry out easily in about 0 ℃ of temperature to about room temperature.
Perhaps, compound of the present invention also can be prepared according to reaction synoptic diagram 2:
Reaction synoptic diagram 2
X wherein 1, R 1, R 3, R 4, R 5And R 6Define during respectively the present invention summarizes freely, PG is the protecting group that is fit to.Therefore, in step 1, acid can with the aminocompound condensation shown in the general formula, produce the beta-hydroxy acid amides.Introduce R again after removing protecting group (step 2) 1Group (step 3) and oxidation (step 4), the compound of production (Ic).
Embodiment:
Following examples have been set forth the preparation according to formula of the present invention (I) compound (embodiment) and intermediate (reference example), and it further specifies the present invention but does not limit the present invention.
1H NMR (Nuclear Magnetic Resonance) spectrum (NMR) is record on Varian Mercury-300 or Unity-400 or UnityPlus-500 or Inova-500 type instrument.In NMR (Nuclear Magnetic Resonance) spectrum (NMR), represent with ppm with respect to the chemical shift (δ) of tetramethylsilane.Abbreviation has following implication: s=is unimodal; D=is bimodal; The t=triplet; The m=multiplet; The q=quartet; The dd=doublet of doublet; Ddd=doublet of doublet bimodal.
High pressure liquid chromatography (HPLC) is carried out on 10 microns of Kromasil, 100A silica gel, 4.6mm ID * 250mm post, adopts heptane/THF/1, and the mixture of 2-ethylene dichloride is a moving phase.
Mass spectrum carries out on Agilent 1100 series or MICROMASS LCT-TOF MS instrument.
The R of thin-layer chromatography (TLC) FValue adopts the Merck silica-gel plate to measure.
Abbreviation
The CBZ-benzyloxycarbonyl
DAST-(diethylamino) sulfur trifluoride
The DCM-methylene dichloride
The DMF-dimethyl formamide
The DMSO-dimethyl sulfoxide (DMSO)
The DTT-dithiothreitol (DTT)
EDCI-N-(3-dimethylaminopropyl)-N ￠-ethyl-carbodiimide hydrochloride
The EDTA-ethylenediamine tetraacetic acid (EDTA)
The EtOAc-ethyl acetate
The HOBT-1-hydroxy benzotriazole hydrate
MeOH-methyl alcohol
The MES-2-morpholino b acid
PyBOP-(benzotriazole-1-base oxygen base) tripyrrole Wan Ji Phosphonium hexafluorophosphate
The THF-tetrahydrofuran (THF)
Reference example 1
(S)-2-benzyloxycarbonyl amino-4-oxo-5-phenylpentanoic acid methyl esters:
At N 2(4.26mmol, 611.1mg) suspension in the 3mL dry THF adds lithiumbromide (8.52mmol, 740mg) solution in the 5mL dry THF to cupric bromide (I) in the atmosphere.Mixture in stirring at room 20min, is cooled to-78 ℃ then.Successively add benzylmagnesium chloride solution (the THF solution of 20wt.%, 4.26mmol, 3.25mL) and (S)-(3.59mmol) solution in the 7mL dry THF of the chloroformyl methyl propionate of 2-benzyloxycarbonyl amino-3-[reference: Synth.Comm 1993,23 (18), 2511-2526].This mixture in-78 ℃ of stirring 30min, is used saturated NH then 4Cl (50mL) termination reaction.With this mixture ethyl acetate (30mL) extracting twice.With the dried over mgso organic layer, concentrate in a vacuum then.Resistates through the 35g silica gel purification, is used EtOAc: heptane (1: 1) wash-out, promptly get (S)- 2-benzyloxycarbonyl-amino-4-oxo-5-phenylpentanoic acid methyl esters(1.07g, 84%).
1H?NMR(CDCl 3)：δ7.4-7.17(m，10H)，5.73(d，J＝8.2Hz，1H)，5.11(s，2H)，4.57(m，1H)，3.7(2xs，5H)，3.24(dd，J＝18.5，4.4Hz，1H)，3.0(dd，J＝18.2，4.1Hz，1H)；LC/MS：100％378(M+Na)。
Reference example 2
(S)-2-benzyloxycarbonyl amino-4-oxo Methylheptanoate
Figure A20048003891200452
Carrying out, but use the propyl group magnesium chloride to replace benzylmagnesium chloride with above-mentioned reference example 1 similar mode, promptly make (S)- 2-benzyloxycarbonyl amino-4-oxo Methylheptanoate
1H?NMR(CDCl 3)：δ7.35(m，5H)，5.78(d，J＝8.5Hz，1H)，5.13(s，2H)，4.58(m，1H)，3.75(s，3H)，3.2(dd，J＝18.3，4.2Hz，1H)，2.96(dd，J＝18.3，4.1Hz，1H)，2.4(m，2H)，1.6(m，2H)，0.92(t，J＝7.4Hz，3H)；LC/MS：330(M+Na)。
Reference example 3
(S)-and 2-benzyloxycarbonyl amino-4,4-two fluoro-5-phenylpentanoic acid methyl esters:
Figure A20048003891200461
With 2-benzyloxycarbonyl amino-4-oxo-5-phenylpentanoic acid methyl esters (3.310g, 9.31mmol) and the mixture of DAST (7mL) in stirring at room 3 days.Mixture is also added 0.5N NaOH solution (150mL) carefully with methylene dichloride (100mL) dilution.With methylene dichloride (50mL) aqueous layer extracted.With the dried over mgso organic layer, concentrate in a vacuum then.Resistates through the 110g silica gel purification, is used EtOAc: heptane (1: 41: 3 then) wash-out, promptly (S)-and 2-benzyloxycarbonyl amino-4,4-two fluoro-5-benzene The base methyl valerate(1.797g, 51.1%).
1H?NMR(CDCl 3)δ7.3(m，10H)，5.43(d，J＝7.6Hz，1H)，5.14(s，2H)，4.65(m，1H)，3.74(s，3H)，3.2(t，J＝16.5Hz，2H)，2.4(m，2H)；LC/MS：97％400(M+Na)。
Reference example 4
(S)-and 2-amino-4,4-two fluoro-5-phenylpentanoic acid methyl ester hydrochlorides:
(S)-2-benzyloxycarbonyl amino-4,4-two fluoro-5-phenylpentanoic acid methyl esters (7.806g, 20.68mmol) dioxane solution of solution in 120mL methyl alcohol and 4M HCl (41.4mmol, 10.3mL) under 50psi pressure through 10%Pd/C (1.0g) hydrogenation.After 8 hours, add a part of 10%Pd/C (1.0g) again.After 24 hours, filter removing catalyzer with the diatomite filter plate, and filtrate is concentrated in a vacuum.The gained faint yellow solid is dissolved in minimum methyl alcohol also to add in the ether (150mL) lentamente.Allow the gained slurry 30min that wears out, filter then.The suction dried white solid, promptly (S)-and 2-amino-4,4-two fluoro-5-phenylpentanoic acid methyl ester hydrochlorides(4.950g, 85.5%).
1H?NMR(DMSO-D6)：δ8.6(b，3H)，7.3(m，5H)，4.26(t，J＝6Hz，1H)，3.73(s，3H)，3.3(t，J＝17.5Hz，2H)，2.55(m，2H)；LC/MS：100％244(M+1)。
Reference example 5
(S)-4,4-two fluoro-2-[(morpholine-4-carbonyls)-amino]-5-phenylpentanoic acid methyl esters:
At N 2In the atmosphere to (S)-2-amino-4,4-two fluoro-5-phenylpentanoic acid methyl ester hydrochlorides (2.50g, 8.94mmol) and Diisopropylamine (22.3mmol, 2.89g) mixture in dry methylene chloride (40mL) drip the morpholine carbonyl chloride (13.4mmol, 2.0g).With this mixture in stirring at room 15 hours, dilute with water (50mL) then.With methylene dichloride (30mL) aqueous layer extracted.With the dried over mgso organic layer, concentrate in a vacuum then.Through the 110g silica gel purification, use EtOAc: heptane (1: 1,2: 1 then) wash-out, promptly (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls)-amino]-5-phenylpentanoic acid methyl esters(2.82g, 88.5%).. 1H?NMR(CDCl 3)：δ7.3(m，5H)，5.16(d，J＝7.5Hz，1H)，4.75(dd，J＝13，6Hz，1H)，3.73(s，3H)，3.7(m，4H)，3.4(m，4H)，3.2(t，J＝16.7Hz，2H)，2.4(m，2H).LC/MS：100％357(M+1)。
Reference example 6
(S)-4,4-two fluoro-2-[(morpholine-4-carbonyls)-amino]-the 5-phenylpentanoic acid:
Figure A20048003891200472
To (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls)-amino]-(2.81g is 7.88mmol) at MeOH: H for 5-phenylpentanoic acid methyl esters 2O (2: 1vol, the solution in 40mL) add the LiOH monohydrate (662mg, 15.76mmol).With this mixture in stirring at room 2.5h, dilute with water (30mL) then.Remove methyl alcohol in a vacuum.With 6N HCl the pH value is adjusted to pH 1 and uses methylene dichloride (2 * 30mL) aqueous layer extracted.With dried over mgso organic layer and concentrated in a vacuum, promptly (S)-4,4-two fluoro-2-[( Quinoline-4-carbonyl)-amino]-the 5-phenylpentanoic acid(2.509g, 93%).
1H?NMR(CDCl 3)：δ8.2(b，1H)，7.3(m，5H)，5.3(m，1H)，4.6(m，1H)，3.65(m，4H)，3.4(m，4H)，3.2(t，J＝16.5Hz，2H)，2.4(m，2H)；LC/MS：94％343(MH +)。
Reference example 7
(S)-5-benzyloxycarbonyl amino-2-sec.-propyl-3-oxo-hexanodioic acid 1-tert-butyl ester 6-methyl esters:
At N 2In the atmosphere to be cooled to-78 ℃ diisopropylamine (3.53g, 34.88mmol) solution in dry THF (20mL) drip n-butyllithium solution (hexane solution of 2.5M, 34.88mmol, 13.95mL).This mixture in-78 ℃ of stirring 30min, is added 3-methyl-tert-butyl acetate (34.88mmol, 5.52g) solution in THF (40mL) then.This mixture is stirred 30min in-78 ℃, drip then (S)-2-benzyloxycarbonyl amino-3-chloroformyl-(reference: Synth.Comm 1993,23 (18), 2511-2526) (16.6mmol) solution in the 30mL dry THF for the propionic acid methyl.After-78 ℃ of restir 2 hours, with the 1N HCl termination reaction of 50mL and be warming up to room temperature.With 1N NaOH the pH value is adjusted to pH 3 and removes THF in a vacuum.With EtOAc (2 * 60mL) extraction organic layers.Concentrate in a vacuum then with the dried over mgso organic layer.Resistates through the 90g silica gel purification, is used EtOAc: heptane (1: 31: 2 then) wash-out, promptly (S)-5-benzyloxycarbonyl amino-2- Sec.-propyl-3-oxygen base hexanodioic acid 1-tert-butyl ester 6-methyl esters(2.417g, 34.5%).
1H?NMR(CDCl 3)：δ7.4(m，5H)，5.73(d，J＝8.4Hz，1H)，5.12(s，2H)，4.6(m，1H)，3.74(s，3H)，3.39-3.06(m，3H)，2.4(m，1H)，1.45(2s，9H)，0.98(d，J＝6.6Hz，3H)，0.88(d，J＝6.7Hz，3H)；LC/MS：100％422(M+1)。
Reference example 8
(S)-2-benzyloxycarbonyl amino-4-oxo-hexanodioic acid 6-tert-butyl ester 1-methyl esters:
Figure A20048003891200491
To N-CBZ L-aspartic acid 1-methyl esters (1.00g, 3.55mmol) solution in dry tetrahydrofuran (17mL) add carbonyl dimidazoles (634.1mg, 3.91mmol).This mixture in stirring at room 6 hours, is added magnesium salts (1.339g, 3.91mmol) (according to the Angew.Chem.Int.Ed.Engl.1979,18 (1), 72-74 preparation) of propanedioic acid list tertiary butyl ester then.This mixture in room temperature restir 20h, is concentrated then in a vacuum.Resistates is distributed between ether (60mL) and 0.5N HCl (60mL).Use saturated NaHCO 3Solution (50mL) washing organic layer is then with dried over mgso and concentrated in a vacuum.Resistates through the 35g silica gel purification, is used EtOAc: heptane (1: 1) wash-out, promptly (S)-2- Benzyloxycarbonyl amino-4-oxo-hexanodioic acid 6-tert-butyl ester 1-methyl esters(1.17g, 87%).
1H?NMR(CDCl 3)：δ7.4(m，5H)，5.73(d，J＝8.3Hz，1H)，5.1(s，2H)，4.6(m，1H)，3.75(s，3H)，3.37(s，2H)，3.32(dd，J＝18.7，4.3Hz，1H)，3.13(dd，J＝18.5，4.1Hz，1H)，1.47(s，9H)；LC/MS：93％402(M+Na)。
Reference example 9
(S)-2-benzyloxycarbonyl amino-6-methyl-4-oxo-Methylheptanoate:
At N 2(1.06g, 2.51mmol) (35.8mg, 0.19mmol) the solution reflux in toluene (20mL) is 6.5 hours with the tosic acid monohydrate with 5-benzyloxycarbonyl amino-2-sec.-propyl-3-oxo-hexanodioic acid 1-tert-butyl ester 6-methyl esters in the atmosphere.This mixture is cooled to room temperature, and concentrates in a vacuum.Resistates through the 35g silica gel purification, is used EtOAc: heptane (1: 4) wash-out, promptly (S)-2- Benzyloxycarbonyl amino-6-methyl-4-oxo-Methylheptanoate(727mg, 90%). 1H?NMR(CDCl 3)：δ7.4(m，5H)，5.78(d，J＝9.1Hz，1H)，5.13(s，2H)，4.6(m，1H)，3.74(s，3H)，3.2(dd，J＝18.3，4.4Hz，1H)，2.95(dd，J＝18.2，4.0Hz，1H)，2.3(m，2H)，2.1(m，1H)，0.92(d，J＝6.7Hz，6H)；LC/MS：77％322(MH +)。
Reference example 10
(S)-2-benzyloxycarbonyl amino-4-oxo-methyl valerate:
Carrying out, but use 2-benzyloxycarbonyl amino-4-oxo hexanodioic acid 6-tert-butyl ester 1-methyl esters, promptly make with above-mentioned reference example 9 similar modes (S)-2-benzyloxycarbonyl amino-4-oxo-methyl valerate 1H?NMR(CDCl 3)：δ7.4(m，5H)，5.76(d，J＝8.1Hz，1H)，5.14(s，2H)，4.57(m，1H)，3.75(s，3H)，3.23(dd，J＝18.4，4.3Hz，1H)，3.0(dd，J＝18.4，4.3Hz，1H)，2.18(s，3H)；LC/MS：＞85％280(MH +)。
The replacement method
At N 2In the atmosphere to the suspension of cupric iodide (I) in ether (20mL) that is cooled to 0 ℃ add lentamente lithium methide (the 1.6M diethyl ether solution, 21.3mmol, 13.3mL).This mixture is stirred 10min in 0 ℃ be cooled to-78 ℃ then.Drip 3.55mmol (S)-2-benzyloxycarbonyl amino-3-chloroformyl-(reference: Synth.Comm 1993,23 (18), 2511-2526) solution in the 12mL dry THF for methyl propionate.This mixture in-78 ℃ of stirring 30min, is added methyl alcohol (2mL) then with termination reaction.Pour this mixture into saturated NH 4Cl (80mL) also uses ether (2 * 40mL) extractions.With dried over mgso organic layer and concentrated in a vacuum.Resistates through the 35g silica gel purification, is used EtOAc: heptane (1: 1) wash-out, promptly (S)-2-benzyloxycarbonyl amino-4-oxo-methyl valerate(261mg, 26%).
Reference example 11
(S)-and 2-benzyloxycarbonyl amino-4,4-two fluoro-6-methyl enanthic acid methyl esters:
Figure A20048003891200511
With (S)-2-benzyloxycarbonyl amino-6-methyl-4-oxo-Methylheptanoate (915mg, 2.85mmol) and DAST (3mL, mixture XS) stirs 47h in-35 ℃.This mixture is also added saturated NaHCO carefully with methylene dichloride (50mL) dilution 3Solution (150mL).With methylene dichloride (30mL) aqueous layer extracted.With dried over mgso organic layer and concentrated in a vacuum.Resistates through the 35g silica gel purification, is used EtOAc: heptane (1: 4) wash-out, promptly get (S)- 2-benzyloxycarbonyl amino-4,4-two fluoro-6-methyl Methylheptanoate(156mg, 16%).
1H?NMR(CDCl 3)：δ7.4(m，5H)，5.48(d，J＝7.9Hz，1H)，5.15(s，2H)，4.61(q，J＝5.9Hz，1H)，3.78(s，3H)，2.4(m，2H)，1.95(m，1H)，1.8(m，2H)，0.98(d，J＝6.6Hz，6H)；LC/MS：98％366(M+Na)。
Reference example 12
(S)-and 2-benzyloxycarbonyl amino-4,4-two fluoro-methyl valerates
Figure A20048003891200512
Carrying out, but use (S)-2-benzyloxycarbonyl amino-4-oxopentanoie acid methyl esters, promptly make with above-mentioned reference example 11 similar modes (S)-and 2-benzyloxycarbonyl amino-4,4-two fluoro-methyl valerates
1H?NMR(CDCl 3)：δ7.4(m，5H)，5.46(d，J＝7.1Hz，1H)，5.15(s，2H)，4.61(q，J＝7.3Hz，1H)，3.78(s，3H)，2.45(m，2H)，1.67(t，J＝18.8Hz，3H)；LC/MS：94％324(M+Na)。
Reference example 13
(S)-and 2-benzyloxycarbonyl amino-4,4-difluoro Methylheptanoate
Figure A20048003891200521
Carrying out, but use (S)-2-benzyloxycarbonyl amino-4-oxo Methylheptanoate with above-mentioned reference example 11 similar modes, promptly make (S)- 2-benzyloxycarbonyl amino-4,4-difluoro Methylheptanoate
LC/MS：96％330(MH +)，352(M+Na)。
Reference example 14
(S)-and 2-amino-4,4-two fluoro-6-methyl enanthic acid methyl ester hydrochlorides:
(S)-2-benzyloxycarbonyl amino-4,4-two fluoro-6-methyl enanthic acid methyl esters (333mg, 0.97mmol) dioxane solution of solution in methyl alcohol (10mL) and 4M HCl (4mmol, 1mL) under 55psi pressure through 10%Pd/C (150mg) hydrogenation.After 7 hours, add a part of 10%Pd/C (200mg) again and recover hydrogenation.5.5 after hour, reaction still gets nowhere.Concentrate and apply hydrogenation conditions in a vacuum with the catalyzer elimination and with filtrate.After 6.5 hours, filter removing catalyzer with the diatomite filter plate, and filtrate is concentrated in a vacuum, promptly (S)-and 2-amino-4,4-two fluoro-6-methyl enanthic acid methyl esters hydrochloric acid Salt, be yellow viscous solid (240mg, quantitative).
1H?NMR(CDCl 3)：δ4.8(b，3H)，4.35(b，1H)，3.84(s，3H)，2.6(m，2H)，1.9(m，3H)，0.99(d，J＝6.2Hz，6H)；LC/MS：90％210(M+1)。
Reference example 15
(S)-and 2-amino-4,4-two fluoro-methyl valerate hydrochlorides:
Figure A20048003891200523
Carrying out with above-mentioned reference example 14 similar modes, but use (S)-2-benzyloxycarbonyl amino-4,4-two fluoro-methyl valerates promptly make (S)-and 2-amino-4,4-two fluoro-methyl valerate hydrochlorides
1H?NMR(CDCl 3)：δ4.8(s，3H)，4.37(m，1H)，3.86(s，3H)，2.4-2.8(m，2H)，1.73(t，J＝18.9Hz，3H)；LC/MS：100％168(M+1)。
Reference example 16
(S)-and 2-amino-4,4-difluoro Methylheptanoate hydrochloride
Carrying out with above-mentioned reference example 14 similar modes, but use (S)-2-benzyloxycarbonyl amino-4,4-difluoro Methylheptanoate promptly makes (S)-and 2-amino-4,4-difluoro Methylheptanoate hydrochlorideLC/MS：100％196(MH +)。
Reference example 17
(S)-4,4-two fluoro-6-methyl-2-[(morpholine-4-carbonyl)-amino]-Methylheptanoate:
Figure A20048003891200532
At N 2In the atmosphere to (S)-2-amino-4,4-two fluoro-6-methyl enanthic acid methyl ester hydrochlorides (238mg, 0.97mmol) and Diisopropylamine (2.42mmol, 313mg) mixture in dry methylene chloride (5mL) drip the morpholine carbonyl chloride (1.45mmol, 218mg).This mixture in stirring at room 23h, is used methylene dichloride (25mL) dilution and then with rare HCl (30mL) and saturated NaHCO 3(30mL) washing.With dried over mgso organic layer and concentrated in a vacuum.Through the 12g silica gel purification, use EtOAc: heptane (1: 1,2: 1 then) wash-out, promptly (S)-4,4-two fluoro-6-methyl-2-[(morpholine-4-carbonyl)-amino]-enanthic acid Methyl esters(206mg, 66%).
1H?NMR(CDCl 3)：δ5.2(d，J＝7.4Hz，1H)，4.72(dd，J＝13，6Hz，1H)，3.78(s，3H)，3.7(m，4H)，3.4(m，4H)，2.4(m，2H)，1.95(m，1H)，1.8(m，2H)，0.99(d，J＝6.4Hz，6H)；LC/MS：90％345(M+Na)。
Reference example 18
(S)-4,4-two fluoro-2-[(morpholine-4-carbonyls)-amino]-methyl valerate:
Figure A20048003891200541
Carrying out, but use (S)-2-amino-4 with above-mentioned reference example 17 similar modes, 4-two fluoro-methyl valerate hydrochlorides, promptly make (S)- 4,4-two fluoro-2-[(morpholine-4-carbonyls)-amino]-methyl valerate
1H?NMR(CDCl 3)：δ5.18(d，J＝7.5Hz，1H)，4.71(q，J＝7Hz，1H)，3.78(s，3H)，3.71(m，4H)，3.4(m，4H)，2.37-2.55(m，2H)，1.67(t，J＝18.7Hz，3H)；LC/MS：100％303(M+Na)。
Reference example 19
(S)-4,4-two fluoro-2-[(morpholine-4-carbonyls)-amino]-Methylheptanoate:
Figure A20048003891200542
Carrying out, but use with above-mentioned reference example 17 similar modes (S)-and 2-amino-4,4-difluoro enanthic acid Methyl ester hydrochloride, promptly make (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls)-amino]-MethylheptanoateLC/MS：100％309(MH +)。
Reference example 20
(S)-4,4-two fluoro-6-methyl-2-[(morpholine-4-carbonyl)-amino]-enanthic acid:
Figure A20048003891200543
(205mg is 0.63mmol) at MeOH: H to methyl esters 2O (2: 1vol, the solution in 4mL) add the LiOH monohydrate (80mg, 1.9mmol).In stirring at room 21h, dilute with water (15mL) is also with ether (20mL) extraction then with this mixture.With 1N HCl the pH value of water layer is adjusted to pH 1 and uses methylene dichloride (2 * 20mL) extractions.With dried over mgso organic layer and concentrated in a vacuum, promptly (S)-4,4-two fluoro-6-methyl-2-[(morpholine-4-carbonyl)-amino]-enanthic acid(168mg, 86%).
1H?NMR(CDCl 3)：δ6.4(b，1H)，5.3(d，J＝6.2Hz，1H)，4.6(m，1H)，3.7(m，4H)，3.4(m，4H)，2.5(m，2H)，2.0(m，1H)，1.8(m，2H)，1.0(d，J＝6.6Hz，6H)；LC/MS：90％309(M+1)。
Reference example 21
(S)-4,4-two fluoro-2-[(morpholine-4-carbonyls)-amino]-valeric acid:
Figure A20048003891200551
Carrying out, but use (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls with above-mentioned reference example 20 similar modes)-amino]-methyl valerate, promptly make (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls)-amino]-valeric acid
1H?NMR(CDCl 3)：δ5.9(b，1H)，5.29(d，J＝6.3Hz，1H)，4.6(m，1H)，3.71(m，4H)，3.4(m，4H)，2.38-2.65(m，2H)，1.70(t，J＝18.9Hz，3H)；LC/MS：100％267(M+1)。
Reference example 22
(S)-4,4-two fluoro-2-[(morpholine-4-carbonyls)-amino]-enanthic acid
Carrying out, but use with above-mentioned reference example 20 similar modes (S)-4,4-two fluoro-2-[(morpholine-4- Carbonyl)-amino]-Methylheptanoate, promptly make (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls)-amino]-enanthic acid
1H?NMR(CDCl 3)：δ5.3(b，1H)，5.25(d，J＝5.4Hz，1H)，4.6(m，1H)，3.71(m，4H)，3.4(m，4H)，2.6-2.3(m，2H)，1.9(m，2H)，1.55(m，2H)，1.0(t，J＝7.3Hz，3H)；LC/MS：83％295(M+1)。
Reference example 23
5-thiophene-2-Ji oxazole
Figure A20048003891200561
At N 2In the atmosphere to the p-toluenesulfonyl methyl-isocyanide (3.0g, 15.36mmol) and thiophene-2-formaldehyde (1.72g, 15.36mmol) solution in methyl alcohol (45mL) add salt of wormwood (2.12g, 15.36mmol).With this mixture reflux 5 hours, cooling and concentrate (cooling bath) in a vacuum then.Resistates is distributed between ether (100mL) and water (100mL).Water (100mL) washing organic layer with dried over mgso, concentrates then in a vacuum.Resistates through the 35g silica gel purification, is used ethyl acetate: heptane (1: 5) wash-out, promptly 5-thiophene-2-Ji oxazole(0.852g, 37%).
1H?NMR(CDCl 3)：δ7.9(s，1H)，7.3(m，2H)，7.2(s，1H)，7.1(dd，J＝5，3.8Hz，1H)；LC/MS：100％152(M+1)。
Reference example 24
(S)-1-[hydroxyl-(5-thiophene-2-Ji oxazole-2-yl)-methyl]-propyl group }-t-butyl carbamate
To 5-thiophene-2-Ji oxazole (0.85g, 5.62mmol) solution in dry THF (4mL) add boron triethyl (1.0M THF solution, 5.62mmol, 5.62mL).With this mixture in stirring at room 45min, be cooled to then-78 ℃ and drip n-Butyl Lithium (the 1.6M hexane solution, 5.62mmol, 3.51mL).This mixture in-78 ℃ of stirring 45min, is added (1-formyl radical propyl group)-t-butyl carbamate (2.81mmol, 0.526g) solution in dry THF (3mL) then lentamente.This mixture is stirred 4h in-78 ℃,, be warming up to 0 ℃ and the ethanolic soln that adds 30mL 10% (vol) HOAc then with termination reaction.This mixture in stirring at room 18 hours, is concentrated then in a vacuum.Resistates through the 90g silica gel purification, is used ethyl acetate: heptane (1: 21: 1 then) wash-out, promptly (S)-1-[hydroxyl-(5-thiophene-2-Ji oxazole-2-yl)-methyl]-propyl group }-t-butyl carbamate(363mg, 38%) is yellow oil.
1H NMR (CDCl 3): δ (isomer mixture) 7.35 (m, 2H), 7.1 (m, 2H), 4.9 (m, 2H), 4.0 (b, 1H), 3.6 (m, 1H), 1.8-1.55 (m, 2H), 1.4 and 1.3 (2s, 9H), 1.0 and 0.9 (2t, J=7.4Hz, 3H): LC/MS:100339 (M+1).
Reference example 25
(S)-2-amino-1-(5-thiophene-2-base oxazole-2-yl)-Ding-1-alcohol hydrochloride
To (S)-1-[hydroxyl-(5-thiophene-2-Ji oxazole-2-yl)-methyl]-propyl group-t-butyl carbamate (361mg, 1.07mmol) solution in dry methylene chloride (3mL) add 4N HCl De dioxane solution (3.0mL, XS).This mixture in stirring at room 16h, is concentrated, promptly then in a vacuum (S)-2-amino-1-(5-thiophene-2-base oxazole-2-yl)-Ding-1-alcohol hydrochloride, be brown solid (quantitatively).
1H?NMR(CDCl 3)：δ7.5(dd，J＝5.2，1.2Hz，1H)，7.4(dd，J＝3.6，1.1Hz，1H)，7.3(s，1H)，7.1(dd，J＝5，3.6Hz，1H)，4.8(m，3H)，3.6(m，2H)，3.3(b，1H)，1.75(m，2H)，1.0(t，J＝7.5Hz，3H)；LC/MS：100％239(M+1)。
Reference example 26
(1-ethyl-2-hydroxyl-3-nitro propyl group)-t-butyl carbamate
Figure A20048003891200572
To (1-formyl radical propyl group)-t-butyl carbamate (1.0g, 5.34mmol) solution in dry THF (10mL) and ethanol successively add Nitromethane 99Min. (3.91g, 64.09mmol) and triethylamine (2.70g, 26.7mmol).This mixture in stirring at room 22h, is concentrated then in a vacuum.Resistates is used ether (50mL) dilution and used dense NH 4Cl (60mL) washing.The ether layer is also concentrated in a vacuum with dried over mgso.Resistates through the 35g silica gel purification, is used ethyl acetate: heptane (1: 3) wash-out, promptly get required alcohol (1.09g, 82%), be faint yellow oily solid.
1H NMR (CDCl 3): δ 4.2-4.8 (m, 4H), 3.15-3.8 (m, 2H), 1.69-1.6 (m, 2H), 1.47 (2xs, 9H), 1.02 and 1.0 (2xt, J=7.1Hz, 3H); The LC/MS:2 isomer amounts to 100%149 (M-BOC+1).
Reference example 27
(1-ethyl-3-nitro-2-trimethyl silicane alcoxyl base propyl group)-t-butyl carbamate
Figure A20048003891200581
At N 2In the atmosphere to (1-ethyl-2-hydroxyl-3-nitro propyl group)-t-butyl carbamate (1.83g, 7.37mmol) and triethylamine (1.49g, 14.75mmol) mixture in dry methylene chloride (25mL) add trimethylsilyl chloride (1.20g, 11.05mmol).This mixture in stirring at room 24h, is washed with dilution of 40mL methylene dichloride and water (40mL) then.With dried over mgso organic layer and concentrated in a vacuum.Resistates through the 110g silica gel purification, is used ethyl acetate: heptane (1: 4) wash-out, promptly (1-ethyl-3-nitro-2-trimethyl silicane alcoxyl base propyl group)-t-butyl carbamate(1.505g, 86%) is water white oil.
1H NMR (CDCl 3): δ 4.4-4.65 (m, 4H); 3.55 (m, 1H), 1.2-1.7 (m, 11H), 0.98 (2xt, J=7.4Hz, 3H), 0.13 (2s, 9H); The LC/MS:2 isomer amounts to 100%221 (M-BOC+1).
Reference example 28
The different propyl group isoxazole-3-base of 1-[(5-)-trimethyl silicane alcoxyl ylmethyl]-propyl group }-t-butyl carbamate
Figure A20048003891200591
At N 2In the atmosphere to (1-ethyl-3-nitro-2-trimethyl silicane alcoxyl base propyl group)-t-butyl carbamate (918mg, 2.86mmol), two isocyanic acids 1, inferior phenyl ester (the 1.38g of 4-, 8.5mmol) and 3-methyl isophthalic acid-butine (586mg, 8.5mmol) adding of the solution in dry toluene (15mL) triethylamine (10).This mixture is heated to 50 ℃ reaches 28h in a sealed vial, be cooled to room temperature then, add entry (1mL), filter then also with this mixture restir 2h.Filtrate concentrated in a vacuum and with resistates through the 35g silica gel purification, use ethyl acetate: heptane (1: 5) wash-out, promptly { 1-[(5-Yi propyl group isoxazole -3-yl)-trimethyl silicane alcoxyl ylmethyl]-propyl group }-t-butyl carbamate(764mg, 72%) is water white oil.
1H NMR (CDCl 3): δ 6.0 (2s 1H), 4.4-4.9 (m, 2H), 3.7 (m, 1H), 3.0 (m, 1H), 1.2-1.6 (m, 17H), 1.0 (m, 3H), 0.11 and 0.1 (2xs, 9H); The LC/MS:2 isomer amounts to 67%271 (M-BOC+1).
Reference example 29
2-amino-1-(the different propyl group isoxazole-3-base of 5-)-Ding-1-alcohol hydrochloride
Figure A20048003891200592
At N 2In the atmosphere to the different propyl group isoxazole-3-base of 1-[(5-)-trimethyl silicane alcoxyl ylmethyl]-propyl group-solution of t-butyl carbamate in dry methylene chloride (5mL) add 4M HCl dioxane solution (5.0mL, XS).This mixture in stirring at room 22h, is concentrated then in a vacuum, promptly get this amine salt (475mg, 99%), be brown solid.
1H?NMR(CDCl 3)：δ6.25(2xs，1H)，5.0(d，J＝3.9Hz，1H)，4.8(d，J＝6.8Hz，1H)，3.4(m，1H)，3.1(m，1H)，1.5-1.7(m，2H)，1.3(d，J＝6.8Hz，6H)；1.0(t，J＝6.7Hz，3H)；LC/MS：100％199(M+1)。
Reference example 30
5-methyl-3-oxazole-5-isoxazole
In 20min with diisobutyl aluminium hydride (1.0M DCM solution, 25.5ml, 25.5mmol) in-78 ℃, be added dropwise to 5-methyl-isoxazole-3-methyl-formiate (3.0gm under stirring, 21.3mmol) in the solution in the 35ml dry methylene chloride, and this reaction mixture stirred 5.5 hours in-78 ℃.Allow reactant be warming up to-40 ℃ also with ice (60gm) termination reaction.After this biphase mixture is warming up to room temperature, add Seignette salt tetrahydrate (100ml saturated aqueous solution).Separates two is used the dichloromethane extraction water layer.Concentrate with the dried over sodium sulfate organic extract liquid and under reduced pressure, promptly The 5-first Isoxazole-3-formaldehyde,Be white solid (1.3gm).
With the p-toluenesulfonyl methyl-isocyanide (1.75gm, 8.97mmol) and salt of wormwood (1.24gm 8.97mmol) adds 5-methyl-isoxazole-3-formaldehyde (1.0gm, the 8.97mmol) solution in the dry methyl alcohol of 35ml, and with this reaction mixture refluxed (90 ℃) 5 hours.Reactant is cooled to room temperature and under reduced pressure concentrated.Resistates is distributed between ether (100ml) and water (200ml).Organic layer separated and use the extracted with diethyl ether water layer.With salt solution and water washing organic extract liquid, also under reduced pressure concentrated with dried over sodium sulfate, promptly get title compound, be band yellow solid (1.25gm).LC/MS：87％，238(M+1)。
Reference example 31
((S)-1-{ hydroxyl-[5-(5-methyl-isoxazole-3-yl)-oxazoles-2-yl]-methyl }-propyl group)-t-butyl carbamate
Figure A20048003891200602
With boron triethyl (1M THF solution, 12ml, 12mmol) add 5-methyl-3-oxazole-5-isoxazole (1.8gm, the 12mmol) solution in the 40ml dry tetrahydrofuran, and with this mixture in stirring at room 15min.This mixture is cooled to-78 ℃, and (2.5M hexane solution, 4.8ml 12mmol), and stir 15min with this mixture in-78 ℃ to drip n-Butyl Lithium.Drip (S)-1-formyl radical propyl group)-t-butyl carbamate (898.7mg; 4.8mmol) solution in the 15ml dry tetrahydrofuran; and this reaction mixture stirred 3 hours in-78 ℃; the ethanolic soln (4% of letting alone to be warming up to-30 ℃ then and using acetate; 250ml) termination reaction; continue to stir 2 hours, be warming up to room temperature simultaneously.Reactant is under reduced pressure concentrated; Resistates is dissolved in ether (250ml) and in stirring at room 1.5 hours.To precipitate elimination; Filtrate is under reduced pressure concentrated.Carry out silica gel column chromatography and separate, the mixture wash-out with methylene dichloride and ethyl acetate promptly gets title compound, is light yellow solid (830mg).LC/MS100％，338(M+1)。
Reference example 32
(S)-2-amino-1-[5-(5-methyl-isoxazole-3-yl)-oxazole-2-yl]-Ding-1-alcohol; Hydrochloride
Figure A20048003891200611
(4M 1 with hydrogenchloride, the 4-dioxane solution, 3.3ml) drip ((S)-1-{ hydroxyl-[5-(5-methyl-isoxazole-3-yl)-oxazoles-2-yl]-methyl }-propyl group)-t-butyl carbamate (0.75gm, 2.22mmol) solution in the 10ml methylene dichloride, and with this reaction mixture in stirring at room 2.5 hours.Dilute this reactant and room temperature restir 1 hour with ether (50ml).Under reduced pressure concentrate, promptly get title compound, be band yellow solid (0.75gm).
1H?NMR[(CD)3SO]：δ8.18(m，3H)，7.84(s，1H)，6.70(s，1H)，4.90(m，1H)，3.58(m，2H)，2.50(s，3H)，1.60(m，2H)，0.90(t，3H)；LC/MS?100％，238(M+1)。
Reference example 33
(S)-2-amino-1-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-Ding-1-alcohol
Figure A20048003891200621
In 0 ℃ of stirring (S)-3-tert-butoxycarbonyl amino-2-hydroxypentanoic acid (2.00g, 8.57mmol) and N-hydroxyl cyclopropyl carbonamidine (1.03g, 10.29mmol) solution in methylene dichloride (20mL) and in batches add 1.25 equivalent N-carbodicyclo hexylimide-N '-methylated polystyrene (1.70mmol/g, 6.30g, 10.72mmol).This reaction mixture was stirred in nitrogen atmosphere 3 hours, be warming up to 15 ℃ simultaneously.This reaction mixture is filtered, with the washed with dichloromethane resin and be evaporated to filtrate dried in a vacuum.[LC/MS?m/z＝338(M+H+Na)]。
Resistates is dissolved in tetrahydrofuran (THF) (20mL) and in microwave reactor (Smith Creator) in 160 ℃ of heating 3min, be cooled to room temperature and be evaporated to dried in a vacuum.[LC/MS?m/z＝320(M+H+Na)]。Resistates is dissolved in methylene dichloride (50mL) and in stirring at room, simultaneously the dichloromethane solution of 50% trifluoroacetic acid of Dropwise 5 0mL.After 3 hours, this reactant is evaporated to dry doubling in a vacuum is dissolved in the 50mL methylene dichloride once more.Add 3 equivalent Silicycle companies triamine-3 and with this mixture in stirred overnight at room temperature.This mixture is filtered and uses washed with dichloromethane.Evaporation in a vacuum promptly gets 1.04g (61% amounts to).[LC/MS?m/z＝198(M+H)]
Perhaps, the deprotection with HCl carries out the BOC protecting group in diox promptly gets (S)-2-amino-1-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-Ding-1-alcohol hydrochloride.
Reference example 34
(S)-2-amino-1-(3-phenyl-1,2,4-oxadiazole-5-yl)-Ding-1-alcohol
(2.00g is 8.57mmol) with N-hydroxyl benzamidine (1.3g, 9.5mmol) solution in methylene dichloride (40mL) in 0 ℃ of stirring (S)-3-tert-butoxycarbonyl amino-2-hydroxypentanoic acid.Add in batches N-carbodicyclo hexylimide-N '-methylated polystyrene (1.90mmol/g, 6g, 11.4mmol).This reaction mixture was stirred in nitrogen atmosphere 1 hour.This reaction mixture is filtered, with the washed with dichloromethane resin and be evaporated to filtrate dried in a vacuum.[LC/MS m/z=352 (M+H +), 296 (M+H +-iso-butylene)].Resistates is dissolved in tetrahydrofuran (THF) (20mL) and in microwave reactor (Smith Creator) in 180 ℃ of heating 3min, be cooled to room temperature and be evaporated to dried in a vacuum.Resistates with purified by flash chromatography (be with gradient 5% to 65% ethyl acetate/heptane wash-out), is obtained product, be white solid [LC/MS m/z=356 (M+Na +), 234 (M+H +-Boc)].
This product is dissolved in methylene dichloride (45mL) and adds trifluoroacetic acid (5mL).After 2 hours, be evaporated to this reactant dried in a vacuum.Resistates is dissolved in the 50mL methylene dichloride once more.Add Silicycle triamine-3 (9.9g, 39mmol) and with this mixture in stirred overnight at room temperature.This mixture is filtered and uses washed with dichloromethane.Filtrate is concentrated in a vacuum, promptly (S)-2-amino-1-(3-phenyl -1,2,4-oxadiazole-5-yl)-Ding-1-alcohol(775mg, 38%) is white solid.
1H?NMR(CDCl 3)：δ8.12-8.06(m，2H)，7.54-7.45(m，3H)，4.93?&?4.75(2xd，J＝5Hz?&?3.5Hz，1H)，3.25&3.11(2xm，1H)，1.78-1.42(2xm，2H)，1.04?&1.01(2x?t，J＝7.5Hz，3H).[LC/MS?m/z＝234(M+H)]。
Reference example 35
(S)-2-amino-1-(5-phenyl-[1,2,4] oxadiazole-3-yl)-Ding-1-alcohol
By synthetic shown in the following reaction synoptic diagram:
(S)-1-[hydroxyl-(N-hydroxyl amino azomethine acyl group (carbamimidoyl))-methyl]-propyl group }-t-butyl carbamate (2)
With (2-cyano group-1-ethyl-2-hydroxyl-ethyl)-t-butyl carbamate (9.53g, methyl alcohol 44mmol) (80ml) solution is cooled to 0 ℃, and use hydroxylamine hydrochloride (3.05g, methyl alcohol (10.2ml) solution-treated of (80ml) solution of methyl alcohol 44mmol) and 25% sodium methoxide solution in succession.After 0 ℃ is stirred 5min, with this reaction mixture in stirring at room 5 hours, evaporation then.Resistates is distributed between ethyl acetate and water.Organic layer separated and with dried over mgso, then vapourisation under reduced pressure.The yellow oil of remnants is separated with middle pressure chromatogram (MPLC), the mixture wash-out with ethyl acetate and heptane, promptly get (S)-1-[hydroxyl-(N-hydroxyl amino azomethine acyl group)-methyl]-propyl group }-t-butyl carbamate (3.5g), be white solid.MS：MH+248。
1-[hydroxyl-(the amino azomethine acyl group of N-benzoyl oxygen base)-methyl]-propyl group }-t-butyl carbamate (3)
Will 1-[hydroxyl-(N-hydroxyl amino azomethine acyl group)-methyl]-propyl group }-t-butyl carbamate (2) (2.5g; 10mmol) solution in methylene dichloride (125ml) is successively used phenylformic acid (1.36g; 11mmol), EDCI (2.14g; 11mmol), HOBT (1.37g; 10mmol) and triethylamine (1.35mL; 11mmol) handle, and in stirred overnight at room temperature.This reaction mixture is successively used saturated sodium bicarbonate solution and water washing, then with Na 2SO 4Drying, vapourisation under reduced pressure again.With resistates with middle pressure chromatographic separation, with 1% triethylamine 2: the eluant solution in the mixture of 3v/v ethyl acetate and heptane, promptly { 1-[hydroxyl Base-(the amino azomethine acyl group of N-benzoyl oxygen base)-methyl]-propyl group }-t-butyl carbamate(850mg), be yellow solid.MS：MH+352。
2-amino-1-(5-phenyl-[1,2,4] oxadiazole-3-yl)-Ding-1-alcohol (5)
With compound (3) (1.5g, 4.3mmol) solution in diglyme microwave reactor (Smith Creator, S00219) in 150 ℃ the heating 40min.In the Genevac vaporizer under 80 ℃ and vacuum condition 3 hours with solvent evaporation, promptly get brown solid.It is dissolved in methylene dichloride (40ml) and with trifluoroacetic acid in room temperature treatment 2 hours.Under reduced pressure with solvent evaporation to doing, rough thing is water-soluble, with the DCM washing, with alkalize water layer and use dichloromethane extraction of 1M NaOH solution.With Na 2SO 4Dry organic layer and vapourisation under reduced pressure, promptly 2-amino-1-(5-phenyl-[1,2,4] Oxadiazole-3-yl)-Ding-1-alcohol(300mg), be the light brown solid.
1H?NMR(CDCl 3)：δ8.14-8.10(m，2H)，7.59-7.47(m，3H)，4.83?&?4.65(d，J＝5Hz，1H)，3.18-3.05(2m，1H)，1.71-1.20(m，2H)，1.05-0.97(2xt，J＝7.2Hz，3H)。
Reference example 36
(S)-2-acetoxy-3-tert-butoxycarbonyl aminovaleric acid
Figure A20048003891200651
(11mmol 1.12g) is dissolved in methylene dichloride (150ml), and gained solution is cooled to 0 ℃ with pyridine (5ml), 4-(dimethylamino) pyridine (0.01g) and diacetyl oxide.(10mmol, 2.33g A), and stir the gained reaction mixture 5 hours to add (S)-3-tert-butoxycarbonyl amino-2-hydroxypentanoic acid immediately.
Add 1M hydrochloric acid (250ml) and this mixture is transferred to separating funnel.Be separated and with ethyl acetate (200ml) aqueous phase extracted three times two.With organic phase difference water (200ml) and salt solution (100ml) washed twice after merging.With the dried over mgso organic phase and with the solvent vapourisation under reduced pressure, promptly (S)-2-acetoxy-3-tert-butoxycarbonyl aminovaleric acid(2.535g, 92%).MS：m/z＝298(M+Na +)，276(M+H +)。
Reference example 37
Acetate (S)-2-tert-butoxycarbonyl amino-1-[N '-(4-trifluoromethoxy benzoyl) diazanyl carbonyl]-butyl ester
Figure A20048003891200661
(1.82mmol, 0.5g A) are dissolved in the 30ml methylene dichloride with (S)-2-acetoxy-3-tert-butoxycarbonyl aminovaleric acid.(3.64mmol, 1.92g B) and with the gained reaction mixture stir 2min to add N-carbodicyclo hexylimide-N '-methylated polystyrene.(1.65mmol, 0.363g C) and with this reaction mixture stirring spend the night to add 4-(trifluoromethoxy) phenylformic acid hydrazides.After 16 hours, LC/MS analyzes and still shows the hydrazides existence.(1.65mmol 1.15g) also continues to stir 8 hours to add the polystyrene methyl isocyanate.This reaction mixture of suction filtration is also under reduced pressure concentrated with filtrate, promptly Second Acid (S)-2-tert-butoxycarbonyl amino-1-[N '-(4-trifluoromethoxy benzoyl) diazanyl carbonyl]-butyl ester, be yellow foam (0.5g, 64%).LC/MS analyzes and still shows some hydrazides existence.MS：m/z＝500(M+Na +)，478(M+H +)。
Reference example 38
Acetate (S)-2-tert-butoxycarbonyl amino-1-[5-(4-Trifluoromethoxyphen-l)-1,3,4-oxadiazole-2-yl]-butyl ester
With above-mentioned gained acetate (S)-2-tert-butoxycarbonyl amino-1-[N '-(4-trifluoromethoxy benzoyl)-diazanyl carbonyl]-butyl ester is divided into 5 parts, reacts as follows respectively:
With acetate (S)-2-tert-butoxycarbonyl amino-1-[N '-(4-trifluoromethoxy benzoyl)-diazanyl carbonyl]-(0.21mmol 0.1g) is dissolved in THF (5ml) to butyl ester, and this solution is injected Smith microwave synthesis reaction vessel.Add the 2-tertbutylimido-2-diethylamino-1 that is stated from polystyrene, 3-dimethyl perhydro-1,2,3-diaza phospha benzene (diazaphosphorine) (1.05mmol, 0.456g, 2.3mmol/g load) and Tosyl chloride (0.25mmol, 0.048g), and with this reaction mixture in microwave synthesizer in 150 ℃ the heating 10min (fixed is held time).
The reaction mixture that suction filtration merges, and wash this resin with the 300ml ethyl acetate.The filtrate that merges is under reduced pressure concentrated.
Crude product is through purified by flash chromatography (Biotage Horizon, the 25M post, crude product is written into the capsule sheet, flow velocity 17ml/min, 12ml/ part, the 120ml gradient is the n-heptane solution of n-heptane solution to 30% ethyl acetate of 0% ethyl acetate, the n-heptane solution of 240ml 30% ethyl acetate, the 60ml gradient is the n-heptane solution of 30 → 50% ethyl acetate, the n-heptane solution of 300ml 50% ethyl acetate), promptly Acetate (S)-and 2-tert-butoxycarbonyl amino-1-[5-(4-Trifluoromethoxyphen-l)-1,3,4-oxadiazole-2-yl]-butyl ester(0.28g, 58%).MS：m/z＝460(M+H +)。
Reference example 39
((S)-1-{ hydroxyl-[5-(4-Trifluoromethoxyphen-l)-1,3,4-oxadiazole-2-yl]-methyl }-propyl group)-t-butyl carbamate
With acetate (S)-2-tert-butoxycarbonyl amino-1-[5-(4-Trifluoromethoxyphen-l)-1,3,4-oxadiazole-2-yl]-(0.61mmol 0.28g) is dissolved in the mixture of THF (10ml) and water (10ml) to butyl ester.(1.22mmol 0.051g) and with this reaction mixture stirs 2h to add lithium hydroxide monohydrate.The vapourisation under reduced pressure solvent also is transferred to resistates the separating funnel that fills 300ml ethyl acetate and 50ml water.Be separated and with salt solution (100ml) washing organic phase two.Use the dried over mgso organic phase then.The vapourisation under reduced pressure solvent is also dry in high vacuum, promptly ((S)-1-{ hydroxyl-[5-(4-Trifluoromethyl phenyl ether Base)-1,3,4-oxadiazole-2-yl]-methyl }-propyl group)-t-butyl carbamate, be yellow oil (0.225g, 89%).MS：m/z＝440(M+Na +)，418(M+H +)。
Reference example 40
(S)-2-amino-1-(5-(4-Trifluoromethoxyphen-l)-1,3,4-oxadiazole-2-yl)-Ding-1-alcohol
Figure A20048003891200681
Will ((S)-1-{ hydroxyl-[5-(4-Trifluoromethoxyphen-l)-1,3,4-oxadiazole-2-yl]-methyl }-propyl group)-(0.54mmol 0.225g) is dissolved in methylene dichloride (9ml) and also handles with trifluoroacetic acid (1ml) t-butyl carbamate.This reaction mixture stirred 4 hours.The vapourisation under reduced pressure solvent.Resistates is dissolved in methylene dichloride (20ml) again and add the Silicycle triamine (5.4mmol, 1.47g).This reaction mixture is stirred 60h (spending weekend).This reaction mixture of suction filtration and with solvent evaporation, promptly (S)-2-amino -1-(5-(4-Trifluoromethoxyphen-l)-1,3,4-oxadiazole-2-yl)-Ding-1-alcohol(0.164g, 96%).MS：m/z＝318(M+H +)。
Reference example 41
2-cyclopropyl-[1,3,4] oxadiazoles
Figure A20048003891200682
With the cyclopropane-carboxylic acid methyl esters (10g, 0.1mol) and hydrazine hydrate (7.3mL, 0.15mol) mixture reflux and also were cooled to room temperature in 28 hours.With this mixture vapourisation under reduced pressure, carry out drying by removing solvent then with methylbenzene azeotropic.Resistates is dissolved in methylene dichloride also with saturated NaCl washing.With anhydrous MgSO 4Dry organic phase, the vapourisation under reduced pressure solvent, promptly The cyclopropane-carboxylic acid hydrazides(4.36g, 44%).
With the cyclopropane-carboxylic acid hydrazides (31.35g, 0.31mol), the mixture reflux of orthoformic acid trimethylammonium ester (300mL) and tosic acid monohydrate (200mg) spends the night.Remove excessive orthoformic acid trimethylammonium ester and methyl alcohol with distillation.The vacuum distilling resistates, promptly 2-cyclopropyl-[1,3,4] oxadiazoles(22g, 64%). 1H?NMR(CDCl 3)：δ8.24(s，1H)，2.2(m，1H)，1.15(m，4H)；LCMS：100％，111(MH +)。
Reference example 42
The 1-[(5-cyclopropyl-[1,3,4] oxadiazole-2-yls)-hydroxymethyl]-propyl group }-t-butyl carbamate
Figure A20048003891200691
With the 2-cyclopropyl-[(2.16g, 19.6mmol) solution in dry THF (100mL) is cooled to-78 ℃ to 1,3,4] oxadiazoles.(1.6M hexane solution, 12.3mL 19.6mmol), and stir 40min with this reaction mixture in-78 ℃ to drip n-Butyl Lithium.Add MgBr 2.OEt 2(5.0692g, 19.6mmol).Appoint this reaction mixture to be warming up to-45 ℃ and stirred 1.5 hours in this temperature.Add (1-formyl radical propyl group)-t-butyl carbamate (3.7g, 19.6mmol) solution in dry THF (40mL).Appoint this reaction mixture to be warming up to-20 ℃ and stirred 3.5 hours in this temperature.Use saturated NH 4Cl solution stops the reaction of this reaction mixture and uses ethyl acetate extraction.With the organic extract liquid of saturated NaCl solution washing merging and with MgSO 4Dry.Vapourisation under reduced pressure solvent and with column chromatography purification of crude thing is with the mixture wash-out of ethyl acetate and heptane, promptly { 1-[(5-cyclopropyl-[1,3,4] Oxadiazole-2-yl)-hydroxymethyl]-propyl group }-t-butyl carbamate(2.83g, 49%).LCMS：298(MH +)。
Reference example 43
(S)-2-amino-1-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)-Ding-1-alcohol; Compound with trifluoroacetic acid
With { 1-[(5-cyclopropyl-[1,3,4] oxadiazole-2-yl)-hydroxymethyl]-propyl group }-t-butyl carbamate (2.83g, 9.95mmol), the mixture of trifluoroacetic acid (5mL) in methylene dichloride (20mL) be in stirring at room 2 hours, and under reduced pressure be concentrated into dried, promptly (S)-2-amino-1-(5-cyclopropyl-1,3,4-Evil two Azoles-2-yl)-compound of Ding-1-alcohol and trifluoroacetic acidLCMS：100％198(MH +)。
Reference example 44
(S)-4,4-two fluoro-2-[(perhydros-1,4-oxygen azepine -4-carbonyl)-amino]-methyl valerate.
Triphosgene is dissolved in methylene dichloride (10mL), in the time of one section 1h, in this solution, add the S-2-amino-4 that is dissolved in methylene dichloride by syringe pump, 4-two fluoro-pentanoic acid hydrochloride salt (1.00g, 4.90mmol) (example 15 sees reference) and diisopropylethylamine (1.88mL, mixture 10.80mmol).After the restir 15min, with high morpholine (homomorpholine) hydrochloride (0.67g, 4.90mmol) and diisopropylethylamine (1.90mL, methylene dichloride 10.90mmol) (10mL) solution adds this solution.With gained solution in stirring at room 2h.Dilute with ethyl acetate (100mL) with solvent evaporation and with resistates, successively use 1M KHSO then 3(2 * 10mL), saturated NaHCO 3With the salt water washing.With Na 2SO 4Dry organic phase, filtration and concentrated promptly get light yellow oil.Rough thing through the 20g silica gel purification, is used ethyl acetate: heptane carries out the 50-100% gradient elution.Promptly (S)-4,4-two fluoro-2-[(perhydros-1, 4-oxygen azepine -4-carbonyl)-amino]-methyl valerate, be white solid (0.40g, 28%).
1H?NMR(CDCl 3)δ5.12(d，J＝7.5Hz，1H)，4.72(dd，J＝12.0，7.2Hz，1H)，3.75(m，7H)，3.55(m，4H)，2.45(m，2H)，1.98(m，2H)，1.66(t，J＝18.7Hz，3H)；LC/MS：295，100％，(M+H)，317(M+Na)。
Reference example 45
(S)-4,4-two fluoro-2-[(perhydros-1,4-oxygen azepine -4-carbonyl)-amino]-valeric acid
Figure A20048003891200702
With (S)-4,4-two fluoro-2-[(perhydros-1,4-oxygen azepine -4-carbonyl)-amino]-(0.38g 1.29mmol) is dissolved in tetrahydrofuran (THF)/methyl alcohol (15mL/10mL) to methyl valerate, and adds lithium hydroxide (35mg, 1.40mmol) aqueous solution (5mL).In this reactant of stirring at room 18h, remove methyl alcohol/tetrahydrofuran (THF) then in a vacuum.(3 * 20mL) extractions are with Na with 6M hydrochloric acid (0.25mL) acidifying resistates and with methylene dichloride 2SO 4Drying concentrates, promptly (S)-4,4-two fluoro-2-[(perhydros-1,4-oxygen azepine -4-carbonyl)- Amino]-valeric acid, be white solid (0.36g, 99%).
1H?NMR(DMSO-d6)δ12.6(bs，1H)，6.60(d，8.3Hz，1H)，4.30(dd，J＝14.5，7.0Hz，1H)，3.57(m，4H)，3.43(m，4H)，2.38(m，2H)，1.77(m，2H)，1.61(t，J＝19.2Hz，3H)；LC/MS：100％281(M+H)。
Reference example 46
(S)-4,4-two fluoro-2-[(perhydros-1,4-oxygen azepine -4-carbonyl)-amino]-Methylheptanoate
Will in nitrogen atmosphere (S)-2-amino-4,4-difluoro Methylheptanoate hydrochloride (5.79g, 0.025mol)Join sodium bicarbonate (5.25g) and (5.03g is 25mmol) in the mixture in acetonitrile (130ml), and in stirring at room 5 hours to the nitroxyl chloride manthanoate.(3.61g 26.25mmol) and triethylamine (12.5ml), and spends the night at this reactant of stirring at room to add high morpholine (homomorpholine) hydrochloride.The vapourisation under reduced pressure solvent distributes rough thing between water (150ml) and ethyl acetate (200ml).Isolate organic layer, successively use K 2CO 3Solution (150ml), HCl (150ml) and salt solution (150ml) washing.Separate organic layer, with MgSO 4Dry also vapourisation under reduced pressure.With column chromatography purification of crude thing, successively use the n-heptane solution and the eluent ethyl acetate of 1: 1 to 8: 2 ethyl acetate of v/v, promptly (S)-4,4-difluoro -2-[(perhydro-1,4-oxygen azepine -4-carbonyl)-amino]-Methylheptanoate(4.8g), be light yellow oil.LC/MS：323(M+H)。
Reference example 47
(S)-4,4-two fluoro-2-[(perhydros-1,4-oxygen azepine -4-carbonyl)-amino]-enanthic acid
Figure A20048003891200721
Carrying out, but use (S)-4,4-two fluoro-2-[(perhydros-1,4-oxygen azepine -4-carbonyl with above-mentioned reference example 45 similar modes)-amino]-Methylheptanoate, promptly make (S) 4,4-two fluoro-2-[(perhydros-1,4-oxygen azepine -4-carbonyl)-amino]-enanthic acidLC/MS：309(M+H)。
Reference example 48
(S)-2-amino-1-(3-sec.-propyl-[1,2,4] oxadiazole-5-yl)-Ding-1-alcohol
Step according to reference example 33 makes in a similar manner.LCMS：200(M+H)。
Reference example 49
(S)-and the 1-[(5-tertiary butyl-1,2,4-oxadiazole-3-yl)-hydroxymethyl]-propyl group }-t-butyl carbamate
Figure A20048003891200723
With trimethylammonium acetic anhydride (0.212ml; 1.04mmol) handle and to contain (S)-1-[hydroxyl-(N-hydroxyl amino azomethine acyl group)-methyl]-propyl group }-t-butyl carbamate (235mg; 0.95mmol) diglyme (2ml), and with this reaction mixture in the EmrysOptimizer microwave instrument that Personal Chemistry company produces in 170 ℃ of heating 5min.Evaporating solvent under condition of high vacuum degree.With the rough thing of purified by flash chromatography gained, with the mixture wash-out of ethyl acetate and heptane (1: 4), promptly (S)-and the 1-[(5-tertiary butyl-1,2,4-oxadiazole-3-yl)-hydroxymethyl]-propyl group }-t-butyl carbamate, be brown oil (100mg) (non-enantiomer mixture).
1H?NMR(CDCl 3)δ：4.92-4.69(m，2H)，4.05-3.85(m，1H)，3.57-3.41?&3.32-3.15(2xbs，1H)，1.73-1.48(m，2H)，1.45?&?1.44(2xs，9H)，1.43?&?1.39(2xs，9H)，0.99?&?0.96(2xt，J＝7.5Hz，3H)；MS：314(M+H)。
Reference example 50
(S)-2-amino-1-(the 5-tertiary butyl-1,2,4-oxadiazole-3-yl)-Ding-1-alcohol
With trifluoroacetic acid (5.18ml, 67.25mmol) handle (S)-the 1-[(5-tertiary butyl-1,2,4-oxadiazole-3-yl)-hydroxymethyl]-propyl group-t-butyl carbamate (2.11g, methylene dichloride 6.72mmol) (20ml) solution, and in stirring at room 3h.The vapourisation under reduced pressure solvent.Resistates is dissolved in methylene dichloride (100ml) and uses PS-Pehanorm (trisamine) (5.38g from Argonaut Technologies, 20.18mmol, the 3.75mmol/g load) handle, with reactant in stirring at room 4 hours, filter and with the filtrate evaporation, promptly (S)-2-amino-1-(the 5-tertiary butyl-1,2,4-oxadiazole-3-yl)-Ding-1-alcohol, be orange oil (975mg) (non-enantiomer mixture).
1H?NMR(CDCl 3)δ：4.73?&?4.58(2xd，J＝5Hz，1H)，3.12-3.00(m，1H)，2.64-2.31(bs，3H)，1.69-1.44(m，2H)，1.43(s，9H)，0.99?&?0.97(2xt，J＝7.5Hz，3H)；MS：214(M+H)。
Reference example 51
(S)-and 1-{[5-(4-fluoro-phenyl)-1,2,4-oxadiazole-3-yl]-hydroxymethyl }-propyl group)-t-butyl carbamate
With (S)-1-[hydroxyl-(N-hydroxyl amino azomethine acyl group)-methyl]-propyl group }-t-butyl carbamate (3g; 0.012mol) and triethylamine (1.54ml; 0.011mol) processing 4-fluorobenzoic acid (1.70g; 0.012mol) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (2.12g, 0.011mol) suspension in methylene dichloride (80ml).With reactant in stirred overnight at room temperature.Then, with the dilution of 40ml methylene dichloride, more successively with unsaturated carbonate salt brine solution (30ml), water (30ml), salt solution (30ml) washing, with Na 2SO 4Dry also vapourisation under reduced pressure solvent.By purified by flash chromatography, the mixture wash-out with ethyl acetate and heptane (2: 1) promptly gets pale solid (2.20g) with resistates.
1H?NMR(CDCl 3)δ：8.10-7.95(m，2H)，7.16-7.00(m，2H)，5.43-5.24(m，2H)，5.22-5.05(m，1H)，5.01-4.85(m，1H)，4.50-4.39(m，1H)，3.80-3.60(m，1H)，1.90-1.78(m，2H)，1.40(s，9H)，0.98(t，J＝7.5Hz，3H)；MS：370(M+H)。
Above gained 240mg solid chemical compound (0.65mmol) is dissolved in diglyme (5ml), and microwave reactor (Smith Creator, S00219) in 160 ℃ the heating 18min.Evaporating solvent under condition of high vacuum degree.With the rough thing of purified by flash chromatography gained, with the mixture wash-out of ethyl acetate and heptane (1: 4), promptly (S)-and 1-{[5-(4-fluoro-phenyl)-1,2,4-oxadiazole-3-yl]-hydroxymethyl }-third Base)-t-butyl carbamate, be white solid (148mg).
1H?NMR(CDCl 3)δ：8.16-8.09(m，2H)，7.25-7.12(m，2H)，4.98-4.73(m，2H)，4.13-3.87(m，1H)，3.82-3.35(m，1H)，1.80-1.52(m，2H)，1.46?&?1.34(2xs，9H)，1.02?&?0.99(2xt，J＝7.5Hz，3H)；MS：352(M+H)。
Reference example 52
(S)-and 2-amino-1-[5-(4-fluoro-phenyl)-1,2,4-oxadiazole-3-yl]-Ding-1-alcohol
Figure A20048003891200751
Step according to above-mentioned reference example 50 makes in a similar manner, but uses (S)-1-{[5-(4-fluoro-phenyl)-1,2,4-oxadiazole-3-yl]-hydroxymethyl }-propyl group)-t-butyl carbamate.
1H?NMR(CDCl 3)δ：8.18-8.05(m，2H)，7.26-7.12(m，2H)，4.92?&?4.73(2xd，J＝5Hz，1H)，3.27-3.05(m，1H)，1.75-1.62(m，1H)，1.59-1.41(m，1H)，1.02?&1.00(2xt，J＝7.5Hz，3H)；MS：252(M+H)。
Reference example 53
(S)-and 1-[(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-hydroxymethyl]-propyl group }-t-butyl carbamate
Figure A20048003891200752
With triethylamine (3.46ml 24.82mmol) handles (S)-1-[hydroxyl-(N-hydroxyl amino azomethine acyl group)-methyl]-propyl group-(6.12g, the 24.78mmol) suspension in methylene dichloride (150ml) is cooled to 0 ℃ to t-butyl carbamate then.Dropping cyclopropyl carbonyl chloride (2.25ml, 24.79mmol).Dilute in this reactant of stirring at room 1h 45min and with the 150ml methylene dichloride.Water (40ml), the saturated bicarbonate aqueous solution (20ml), water (20ml) washing successively is with Na 2SO 4Dry also vapourisation under reduced pressure solvent promptly gets white solid (7.16g).MS：338(M+Na)。
(7.45g, 0.024mol) the solution reflux in the Zai diox (150ml) is 15 hours with above gained compound.Vapourisation under reduced pressure solvent and with the purified by flash chromatography resistates is with the mixture wash-out of ethyl acetate and heptane, promptly (S)-and 1-[(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-hydroxymethyl]-third Base }-t-butyl carbamate, be light yellow solid (5g).
1H?NMR(CDCl 3)δ：4.94-4.74(m，2H)，3.97?&?3.85(2xm，1H)，3.62?&?3.48(2xbs，1H)，2.19(m，1H)，1.72-1.42(m，2H)，1.44?&?1.39(2xs，9H)，1.26-1.18(m，4H)，0.98?&?0.95(2xt，J＝7.4Hz，3H)；MS：298(M+H)。
Reference example 54
(S)-2-amino-1-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-Ding-1-alcohol hydrochloride
Figure A20048003891200761
With 4N HCl De dioxane solution (43ml, in 0.172mmol) (S)-1-[(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-hydroxymethyl]-propyl group-(3.41g, 0.011mmol) solution was in stirring at room 2 hours for t-butyl carbamate.The vapourisation under reduced pressure solvent.With the mixture development of resistates and ethyl acetate and ether, filter then, promptly (S)-2-amino-1-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)- Fourth-1-alcohol hydrochloride, be brown solid (2.47g).
1H?NMR(CDCl 3)δ：8.21(bs，2H)，5.37?&?5.14(2xd，1H)，3.88?&?3.73(2xm，1H)，2.21(m，1H)，1.92-1.50(m，2H)，1.24(m，4H)，1.08?&?1.06(2xt，J＝7.4Hz，3H)；MS：198(M+H)。
Embodiment 1
Morpholine-4-formic acid (S)-1-[(S)-and 1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides
Figure A20048003891200762
With PyBOP (113mg, 0.87mmol) adding (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls)-amino]-enanthic acid (104mg, 0.35mmol), (S)-2-amino-1-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-and Ding-1-alcohol hydrochloride (86.7mg, 0.37mmol) and Diisopropylamine (219mg, 0.42mmol) mixture in dry methylene chloride (5mL).This mixture was also evaporated in stirring at room in 16 hours in a vacuum.Also use saturated NaHCO in succession with ethyl acetate (25mL) dilution resistates 3(30mL), rare HCl (30mL) and saturated NaHCO 3(30mL) washing.With dried over mgso organic layer and concentrated in a vacuum.Through 12g silica gel purification resistates, use ethyl acetate: heptane (2: 11: 0 then) wash-out, promptly Morpholine-4-formic acid (the 1-{1-[(3-cyclopropyl-[1,2,4] oxadiazole-5-yls)-hydroxymethyl]-the propyl group carbamyl Base }-3,3-difluoro hexyl)-acid amides(146mg, 88%) is white solid.LC/MS shows 2 kinds of isomer, amounts to 100%M+1474.
At N 2In the atmosphere; with the DMP (dichloromethane solution of 15%wt; 1.73g; 0.061mmol) adding morpholine-4-formic acid (1-{1-[(3-cyclopropyl-[1; 2; 4] oxadiazole-5-yl)-hydroxymethyl]-the propyl group formamyl }-3,3-difluoro hexyl)-(145mg is 0.31mmol) in the solution in dry methylene chloride (3mL) for acid amides.This reactant in stirring at room 2 hours, is used Na then 2S 2O 3(193mg is 1.22mmol) at saturated NaHCO 3Solution termination reaction (30mL).With methylene dichloride (2 * 30mL) aqueous layer extracted.With dried over mgso organic layer and concentrated in a vacuum.Through 12g silica gel purification resistates, use ethyl acetate: heptane (1: 12: 1 then) wash-out, promptly get required ketone (119mg, 81%), be brown solid.
1H NMR (CDCl 3): δ 7.4 (d, 7.0Hz, 1H), 5.27 (m, 1H), 5.13 (d, J=6.9Hz, 1H), 4.65 (dd, J=13.1,6.9Hz, 1H), 3.7 (m, 4H), 3.4 (m, 4H), 2.4 (m, 2H), 2.2 (m, 1H), 2.05 (m, 1H), 1.8 (m, 3H), 1.55 (m, 2H), 1.15 (m, 4H), 0.98 (t, J=7.4Hz, 6H); LC/MS:28%512 (M+H 2O+Na) and 68%494 (M+Na).
Embodiment 2
Morpholine-4-formic acid (S)-1-[(S)-and 1-(5-cyclopropyl-1,3,4-oxadiazole-2-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides
With PyBOP (171.73mg, 0.33mmol), diisopropylethylamine (0.0575ml, 0.33mmol) and (S)-2-amino-1-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)-Ding-1-alcohol adds (S)-4 with the compound (0.30mmol) of trifluoroacetic acid, 4-two fluoro-2-[(morpholine-4-carbonyls)-amino]-enanthic acid (88.29mg, 0.30mmol) in the solution in dry methylene chloride (4ml), with this reaction mixture in stirred overnight at room temperature.Use the sodium bicarbonate aqueous solution termination reaction, with dichloromethane extraction twice, with dried over sodium sulfate organic extract liquid and vapourisation under reduced pressure.Carry out silica gel column chromatography and separate, with the mixture wash-out of methylene dichloride and ethyl acetate, promptly Morpholine-4-formic acid ((S)-1-{ (S)-1-[(5-cyclopropyl-1,3,4-oxadiazole-2- Base)-hydroxymethyl]-propyl group formamyl-3,3-difluoro hexyl)-acid amides, be white solid (87mg).LC/MS?97％，474(M+1)。
With DMP (15wt%DCM solution; 0.79gm; 0.28mmol) adding morpholine-4-formic acid ((S)-1-{ (S)-1-[(5-cyclopropyl-1; 3; 4-oxadiazole-2-yl)-hydroxymethyl]-the propyl group formamyl }-3; 3-difluoro hexyl)-acid amides (67mg, 0.14mmol) in the solution in dry methylene chloride (10ml), and in stirring at room 2.5 hours.Use NaHCO 3Na in the aqueous solution 2S 2O 3(110.68mg, 0.70mmol) solution termination reaction.Organic layer separated and use the dichloromethane extraction water layer.With dried over sodium sulfate organic extract liquid and under reduced pressure concentrated.Carry out silica gel column chromatography and separate, with the mixture wash-out of methylene dichloride and ethyl acetate, promptly Morpholine-4-formic acid (S)-1-[(S)-1-(5-cyclopropyl-1,3,4-Evil two Azoles-2-carbonyl)-and the propyl group formamyl]-3,3-difluoro hexyl }-acid amides, be white powder (48mg).
1H?NMR(CDCl 3)：δ7.52(d，J＝7.5Hz，1H)，5.34(m，1H)，5.18(d，J＝7.5Hz，1H)，4.65(m，1H)，3.72(m，4H)，3.40(m，4H)，2.50-2.22(m，3H)，2.18-2.08(m，1H)，1.96-1.78(m，3H)，1.60-1.45(m，2H)，1.30(m，4H)，0.98(t+t，6H)；LC/MS?95％，472(M+1)。
Embodiment 3
Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{ (S)-1-[5-(4-Trifluoromethoxyphen-l)-1,3,4-oxadiazole-2-carbonyl]-the propyl group formamyl }-hexyl)-acid amides.
Figure A20048003891200791
With PyBOP (68.69mg, 0.13mmol), diisopropylethylamine (0.023ml, 0.13mmol) and (S)-2-amino-1-[5-(4-Trifluoromethoxyphen-l)-1,3,4-oxadiazole-2-yl]-Ding-1-alcohol (38.0mg 0.12mmol) adds (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls)-amino]-enanthic acid (34mg, 0.12mmol) in the solution in dry methylene chloride (4ml), and with this reaction mixture in stirred overnight at room temperature.Use NaHCO 3Aqueous solution termination reaction is with dichloromethane extraction twice, with Na 2SO 4Dry organic extract liquid and vapourisation under reduced pressure.Carry out silica gel column chromatography and separate, with the mixture wash-out of methylene dichloride and ethyl acetate, promptly Morpholine-4-formic acid [(S)-3,3-two fluoro-1-((S)-1-{ hydroxyl-[5-(4-trifluoromethoxy Phenyl)-1,3,4-oxadiazole-2-yl]-methyl }-the propyl group formamyl)-hexyl]-acid amides, be white solid (61mg).LC/MS?71％，M+1＝594。
With DMP (15wt%DCM solution; 0.58gm; 0.21mmol) add morpholine-4-formic acid [(S)-3; 3-two fluoro-1-((S)-1-{ hydroxyl-[5-(4-Trifluoromethoxyphen-l)-1; 3; 4-oxadiazole-2-yl]-methyl }-the propyl group formamyl)-hexyl]-acid amides (61mg, 0.10mmol) in the solution in dry methylene chloride (8ml), and in stirring at room 3 hours.Use Na 2S 2O 3(81.43mg, NaHCO 0.50mmol) 3Aqueous solution termination reaction.Organic layer separated and use the dichloromethane extraction water layer.With dried over sodium sulfate organic extract liquid and under reduced pressure concentrated.Carry out silica gel column chromatography and separate, with the mixture wash-out of methylene dichloride and ethyl acetate, promptly Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{ (S)-1-[5-(4-trifluoro P-methoxy-phenyl)-1,3,4-oxadiazole-2-carbonyl]-the propyl group formamyl }-hexyl)-acid amides, be white powder (39mg).
1H?NMR(CDCl 3)：δ8.25(d，J＝7.5Hz，2H)，7.60(d，J＝7.5Hz，1H)，7.42(d，J＝7.5Hz，2H)，5.36(m，1H)，5.16(d，J＝7.5Hz，1H)，4.70(m，1H)，3.74(m，4H)，3.42(m，4H)，2.54-2.32(m，2H)，2.28-2.14(m，1H)，2.02-1.80(m，3H)，1.60-1.45(m，2H)，1.06(t，J＝7Hz，3H)，0.96(t，J＝7Hz，3H)；LC/MS：96％，592(M+1)。
Embodiment 4
Morpholine-4-formic acid (S)-1-[(S)-and 1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-two fluoro-4-phenyl-butyl }-acid amides
Figure A20048003891200801
Carrying out, but use (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls with the foregoing description 1 similar mode)-amino]-5-phenylpentanoic acid and (S)-2-amino-1-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-Ding-1-alcohol, promptly make Morpholine-4-formic acid (S)-1-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group amino Formyl radical]-3,3-two fluoro-4-phenyl-butyl }-acid amides
1H NMR (CDCl 3): δ 7.3 (m, 6H), 5.25 (m, 1H), 5.08 (d, J=6.9Hz, 1H), 4.7 (dd, J=12.8,7.4Hz, 1H), 3.7 (m, 4H), 3.4 (m, 4H), 3.2 (t, 16.8Hz, 2H), 2.4-2.1 (m, 3H), 2.05 (m, 1H), 1.8 (m, 1H), 1.1 (m, 4H), 0.95 (t, J=7.5Hz, 3H); LC/MS:35%560 (M+H 2O+Na) and 65%542 (M+Na).
Embodiment 5
Morpholine-4-formic acid 1-[1-(3-cyclopropyl-[1,2,4] oxadiazole-5-carbonyl)-propyl group formamyl] and-3,3-two fluoro-5-methyl-hexyls }-acid amides
Figure A20048003891200802
Carrying out, but use (S)-4,4-two fluoro-6-methyl-2-[(morpholine-4-carbonyl with the foregoing description 1 similar mode)-amino]-enanthic acid and (S)-2-amino-1-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-Ding-1-alcohol, promptly make Morpholine-4-formic acid 1-[1-(the 3-cyclopropyl-[1,2,4] oxadiazole-5-carbonyls)-the amino first of propyl group Acyl group]-3,3-two fluoro-5-methyl-hexyls }-acid amides
1H NMR (CDCl 3): δ 7.6 (d, J=6.8Hz, 1H), 5.2 (m, 2H), 4.66 (dd, J=13,7.2Hz, 1H), 3.7 (m, 4H), 3.4 (m, 4H), 2.3 (m, 2H), 2.2 (m, 1H), 2.05 (m, 1H), 1.95 (m, 1H), 1.8 (m, 3H), 1.1 (m, 4H), 0.97 (d, J=6.6Hz, 6H), 0.96 (t, J=7.4Hz, 3H); LC/MS:26%, 526 (M+H 2O+Na) and 74%, 508 (M+Na).
Embodiment 6
Morpholine-4-formic acid (S)-1-[(S)-and 1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-difluoro butyl }-acid amides
Carrying out, but use (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls with the foregoing description 1 similar mode)-amino]-valeric acid and (S)-2-amino-1-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-Ding-1-alcohol, promptly make Morpholine-4-formic acid (S)-1-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group carbamyl Base]-3,3-difluoro butyl }-acid amides
1H NMR (CDCl 3): δ 7.47 (d, J=6.8Hz, 1H), 5.3 (m, 1H), 5.16 (d, J=6.9Hz, 1H), 4.65 (dd, J=13,7.4Hz, 1H), 3.7 (m, 4H), 3.4 (m, 4H), 2.4 (m, 2H), 2.2 (m, 1H), 2.05 (m, 1H), 1.8 (m, 1H), 1.67 (t, 18.7Hz, 3H), 1.1 (m, 4H), 0.97 (t, J=7.5Hz, 3H); LC/MS:37%484 (M+H 2O+Na) and 63%484 (M+CH 3CN).
Embodiment 7
Morpholine-4-formic acid (S)-3,3-two fluoro-1-[(S)-1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-butyl }-acid amides
Figure A20048003891200821
Carrying out, but use (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls with the foregoing description 1 similar mode)-amino]-valeric acid and (S)-2-amino-1-(3-phenyl-1,2,4-oxadiazole-5-yl)-Ding-1-alcohol, promptly make Morpholine-4-formic acid (S)-3,3-two fluoro-1-[(S)-1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl group amino Formyl radical]-butyl }-acid amides, be light brown solid.
1H NMR (CDCl 3): δ 8.15 (dd, J=7.7,1.5Hz, 2H), 7.61 (d, J=6.4Hz, 1H), 7.5 (m, 3H), 5.35 (m, 1H), 5.2 (d, J=6.9Hz, 1H), 4.68 (dd, J=13.2,7.8Hz, 1H), 3.7 (m, 4H), 3.4 (m, 4H), 2.4 (m, 2H), 2.2 (m, 1H), 1.95 (m, 1H), 1.66 (t, 18.7Hz, 3H), 1.03 (t, J=7.5Hz, 3H); LC/MS:37%520 (M+H 2O+Na) and 63%502 (M+Na).
Embodiment 8
Morpholine-4-formic acid (S)-3,3-two fluoro-1-[(S)-1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl group formamyl]-butyl }-acid amides
Carrying out, but use (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls with the foregoing description 1 similar mode)-amino]-valeric acid and (S)-2-amino-1-(5-phenyl-[1,2,4] oxadiazole-3-yl)-Ding-1-alcohol, promptly make Morpholine-4-formic acid (S)-3,3-two fluoro-1-[(S)-1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl group amino Formyl radical]-butyl }-acid amides
1H NMR (CDCl 3): δ 8.2 (d, J=7.1Hz, 2H), 7.65 (d, J=7.4Hz, 1H), 7.55 (m, 3H), 5.4 (dd, J=12.2,7Hz, 1H), 5.3 (d, J=7.4Hz, 1H), 4.7 (dd, J=13,7.3Hz, 1H), 3.7 (m, 4H), 3.4 (m, 4H), 2.4 (m, 2H), 2.1 (m, 1H), 1.9 (m, 1H), 1.67 (t, 18.7Hz, 3H), 1.0 (t, J=7.4Hz, 3H); LC/MS:6%520 (M+H 2O+Na) and 94%502 (M+Na).
Embodiment 9
Morpholine-4-formic acid 1-[1-(5-cyclopropyl-[1,3,4] oxadiazole-2-carbonyl)-propyl group formamyl] and-3,3-two fluoro-4-phenyl-butyl }-acid amides:
Carrying out, but use (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls with the foregoing description 1 similar mode)-amino]-5-phenylpentanoic acid and (S)-2-amino-1-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)-Ding-1-alcohol trifluoroacetate, promptly make Morpholine-4-formic acid 1-[1-(the 5-cyclopropyl-[and 1,3,4] oxadiazole-2-carbonyls)-third The base formamyl]-3,3-two fluoro-4-phenyl-butyl }-acid amides
1H NMR (CDCl 3): δ 7.3 (m, 6H), 5.27 (m, 1H), 5.0 (d, J=7.0Hz, 1H master), 4.95 (d, J=7.3Hz, 1H times), 4.7 (m, 1H), 3.7 (m, 4H), 3.4 (m, 4H), 3.2 (t, 16.3Hz, 2H), 2.4-2.2 (m, 3H), 2.05 (m, 1H), 1.8 (m, 1H), 1.2 (m, 4H), 0.95 (t, J=7.5Hz, 3H); LC/MS:12%560 (M+H 2O+Na) and 83%542 (M+Na).
Embodiment 10
Morpholine-4-formic acid 3,3-two fluoro-1-[1-(the different propyl group isoxazole of 5--3-carbonyl)-propyl group formamyl]-hexyl }-acid amides:
Figure A20048003891200832
Carrying out, but use 2-amino-1-(the different propyl group isoxazole-3-base of 5-)-Ding-1-alcohol hydrochloride to replace (S)-2-amino-1-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-Ding-1-alcohol hydrochloride, promptly make with the foregoing description 1 similar mode Morpholine-4-formic acid 3,3-two fluoro-1-[1-(the different propyl group isoxazole of 5--3-carbonyl)-propyl group Formamyl]-hexyl }-acid amides, be white solid.
1H NMR (CDCl 3): 2: 1 isomer mixtures 7.4 of δ ca (b, 1H), 6.37 (s, 1H), 5.4 (m, 1H), (5.26 d, J=6.9Hz, 1H master), 5.2 (d, J=7.2Hz, 1H times), 4.7 (m, 1H), 3.7 (m, 4H), 3.4 (m, 4H), 3.15 (m, 1H), 2.4 (m, 2H), 2.1 (m, 1H), 1.8 (m, 4H), 1.5 (m, 1H), 1.35 (d, J=7.0Hz, 6H), 0.95 (m, 6H); LC/MS:100%473 (M+1).
Embodiment 11
Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{1-[5-(5-methyl-isoxazole-3-yl)-oxazole-2-carbonyl]-the propyl group formamyl }-hexyl)-acid amides
Figure A20048003891200841
Carrying out, but use (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls with the foregoing description 3 similar modes)-amino]-enanthic acid and (S)-2-amino-1-[5-(5-methyl-isoxazole-3-yl)-oxazole-2-yl]-Ding-1-alcohol hydrochloride, promptly make Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{1-[5-(5-methyl-isoxazole-3-yl)-oxazole-2- Carbonyl]-the propyl group formamyl }-hexyl)-acid amides, be white solid.
1H?NMR(CDCl 3)：δ7.78(s，1H)，7.40(m，1H)，6.44(s，1H)，5.48(m，1H)，5.22-5.10(m，1H)，4.68(m，1H)，3.72(m，4H)，3.40(m，4H)，2.54(s，3H)，2.50-2.30(m，2H)，2.22-2.08(m，1H)，1.94-1.78(m，3H)，1.60-1.46(m，2H)，1.08-0.94(2xt，6H)；LC/MS：99％，512(M+1)。
Embodiment 12
Morpholine-4-formic acid (S)-3,3-two fluoro-1-[(S)-1-(oxazole-2-carbonyl)-propyl group formamyl]-4-phenyl-butyl }-acid amides
Figure A20048003891200851
Carrying out, but use (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls with the foregoing description 2 similar modes)-amino]-5-phenylpentanoic acid and (S)-2-amino-1-oxazole-2-Ji-Ding-1-alcohol hydrochloride, promptly make Morpholine -4-formic acid (S)-3,3-two fluoro-1-[(S)-1-(oxazole-2-carbonyl)-propyl group formamyl]-4-phenyl-Ding Base }-acid amides
1H?NMR(CDCl 3)：δ7.86(s，1H)，7.37(s，1H)，7.30(m，5H)，7.24(m，1H)，5.45(m，1H)，5.08(d，J＝9Hz，1H)，4.70(m，1H)，3.72(m，4H)，3.38(m，4H)，3.22(t，J＝17Hz，2H)，2.35(m，2H)，2.12(m，1H)，1.85(m，1H)，0.95(t，J＝9Hz，3H)；LC/MS：97％，479(M+1)。
Embodiment 13
Morpholine-4-formic acid (S)-3,3-two fluoro-4-phenyl-1-[(S)-1-(5-thiophene-2-base oxazole-2-carbonyl)-propyl group formamyl]-butyl }-acid amides
Figure A20048003891200852
Carrying out, but use (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls with the foregoing description 1 similar mode)-amino]-5-phenylpentanoic acid and (S)-2-amino-1-(5-thiophene-2-base oxazole-2-yl)-Ding-1-alcohol hydrochloride, promptly make Morpholine-4-formic acid { (S)-3,3-two fluoro-4-phenyl-1-[(S)-1-(5-thiophene-2-base oxazole-2- Carbonyl)-the propyl group formamyl]-butyl }-acid amides
1H?NMR(CDCl 3)：δ7.53(dd，J＝3.6，1Hz，1H)，7.48(dd，J＝5，1Hz，1H)，7.4(s，1H)，7.3(m，6H)，7.15(dd，J＝5，3.6Hz，1H)，5.4(m，1H)，5.15(d，J＝7.1Hz，1H)，4.7(dd，J＝13，7.4Hz，1H)，3.7(m，4H)，3.4(m，4H)，3.2(t，16.7Hz，2H)，2.4(m，2H)，2.1(m，1H)，1.8(m，1H)，0.96(t，J＝7.5Hz，3H)；LC/MS：100％561(M+1)。
Embodiment 14
Morpholine-4-formic acid (S)-1-[(S)-and 1-(benzoxazole-2-carbonyl)-butyl formamyl]-3,3-two fluoro-4-phenyl-butyl }-acid amides
Carrying out, but use (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls with the foregoing description 1 similar mode)-amino]-5-phenylpentanoic acid and (S)-2-amino-1-benzoxazole-2-base-penta-1-alcohol, promptly make Morpholine -4-formic acid (S)-1-[(S)-and 1-(benzoxazole-2-carbonyl)-butyl formamyl]-3,3-two fluoro-4-phenyl- Butyl }-acid amides
1H?NMR(CDCl 3)：δ7.9(d，J＝8.0Hz，1H)，7.66(d，J＝8Hz，1H)，7.56(t，J＝7.2Hz，1H)，7.47(t，J＝8Hz，1H)，7.2(m，6H)，5.6(m，1H)，5.05(d，J＝7Hz，1H)，4.71(dd，J＝12.8，7.4Hz，1H)，3.7(m，4H)，3.35(m，4H)，3.18(t，J＝16.8Hz，2H)，2.3(m，2H)，2.1(m，1H)，1.8(m，1H)，1.4(m，2H)，0.94(t，J＝7.3Hz，3H)；LC/MS：100％543(M+1)。
Embodiment 15
Morpholine-4-formic acid [1-(2-benzoxazole-2-base-1-methoxymethyl-2-oxo-ethylamino formyl radical)-3,3-two fluoro-4-phenyl-butyl]-acid amides
Carrying out, but use (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls with the foregoing description 1 similar mode)-amino]-5-phenylpentanoic acid and (S)-2-amino-1-benzoxazole-2-base-3-methoxyl group-third-1-alcohol, promptly make Morpholine-4-formic acid [1-(2-benzoxazole-2-base-1-methoxymethyl-2-oxo-ethylamino formyl Base)-3,3-two fluoro-4-phenyl-butyl]-acid amides
1H NMR (CDCl 3): δ 7.9 (d, J=7.7Hz, 1H), 7.67 (d, J=8Hz, 1H), 7.56 (t, J=8Hz, 1H), 7.48 (t, J=8Hz, 1H), 7.2 (m, 6H), 5.7 (m, 1H), 5.1 (d, J=7Hz, 1H masters), 5.05 (d, J=7.3Hz, 1H time), 4.8 (m, 1H), 4.26 (dd, J=9.7,3.5Hz, 1H), 3.8 (m, 1H), 3.7 (m, 4H), 3.35 (m, 4H), 3.27 (s, 3H), 3.22 (t, J=16.2Hz, 2H), 2.4 (m, 2H); LC/MS:94%545 (M+1).
Embodiment 16
Morpholine-4-formic acid (S)-1-[(S)-and 1-(benzoxazole-2-carbonyl)-1-methyl-butyl formamyl]-3,3-two fluoro-4-phenyl-butyl }-acid amides
With (S)-2-amino-1-benzoxazole-2-base-2-methyl-penta-1-keto hydrochloride (80.6mg, 0.3mmol), (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls)-amino]-5-phenylpentanoic acid (0.102mg, 0.3mmol), EDCI (69mg, 0.36mmol), HOBT (48.6mg, 0.36mmol) and the mixture of diisopropylethylamine (0.2mL) in DMF in stirred overnight at room temperature.Dilute this reaction mixture with ethyl acetate, successively use cold 1N HCl, saturated NaHCO 3With saturated NaCl solution washing.With dried over mgso organic phase and vapourisation under reduced pressure solvent, promptly get crude product.With the silica gel column chromatography purifying, with the mixture wash-out of ethyl acetate and heptane, promptly Morpholine-4-formic acid (S)-1-[(S)-1-(benzene And oxazole-2-carbonyl)-and 1-methyl-butyl formamyl]-3,3-two fluoro-4-phenyl-butyl }-acid amides(82%).
1H?NMR(CDCl 3)：δ7.8(d，J＝7.8.0Hz，1H)，7.64(d，J＝7.8Hz，1H)，7.53(dt，J＝7.2，1.2Hz，1H)，7.43(dt，J＝8，1.2Hz，1H)，7.2(m，6H)，4.9(d，J＝7.3Hz，1H)，4.65(m，1H)，3.7(m，4H)，3.3(m，4H)，3.1(t，J＝16.8Hz，2H)，2.2(m，3H)，2.1(m，1H)，1.74(s，3H)，1.25(m，2H)，0.9(t，J＝7.3Hz，3H)；LC/MS：100％557(M+1)。
Embodiment 17
Morpholine-4-formic acid [(S)-and 1-((S)-1-cyano group-3-phenyl propyl formamyl)-3,3-two fluoro-4-phenyl-butyl]-acid amides
The PyBOP coupling method that provides according to embodiment 1 carries out, but uses (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls)-amino]-5-phenylpentanoic acid and (S)-2-amino-4-phenylbutyronitrile hydrochloride, promptly make Morpholine -4-formic acid [(S)-and 1-((S)-1-cyano group-3-phenyl propyl formamyl)-3,3-two fluoro-4-phenyl-butyl]- Acid amides
1H?NMR(CDCl 3)：δ7.9(d，J＝7.6Hz，1H)，7.2(m，10H)，5.1(d，J＝7.3Hz，1H)，4.6(m，2H)，3.6(m，4H)，3.3(m，4H)，3.2(t，J＝16.5Hz，2H)，2.74(t，J＝7.2H，2H)，2.3(m，2H)，2.1(m，2H)；LC/MS：100％485(M+1)。
Embodiment 18
Morpholine-4-formic acid [(S)-and 1-(cyano methyl-formamyl)-3,3-two fluoro-4-phenyl-butyl]-acid amides
Figure A20048003891200891
The PyBOP coupling method that provides according to embodiment 1 carries out, but uses (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls)-amino]-5-phenylpentanoic acid and aminoacetonitriles hydrochloride, promptly make Morpholine-4-formic acid [(S)-and 1-(cyano methyl-formamyl)-3,3-two fluoro-4-phenyl-butyl]-acid amides
1H?NMR(CDCl 3)：δ7.95(b，1H)，7.3(m，5H)，5.25(d，J＝7.0Hz，1H)，4.7(dd，J＝12.7，7.2Hz，1H)，4.1(m，2H)，3.7(m，4H)，3.35(m，4H)，3.2(t，J＝16.3Hz，2H)，2.4(m，2H)；LC/MS：83％403(M+Na)。
Embodiment 19
Morpholine-4-formic acid [(S)-3,3-two fluoro-1-((S)-1-formyl radical-1-methyl-butyl formamyl)-4-phenyl-butyl]-acid amides
Figure A20048003891200892
With (S)-2-amino-2-methyl-penta-1-alcohol hydrochloride (104.4mg, 0.67mmol), (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls)-amino]-5-phenylpentanoic acid (231mg, 0.67mmol), EDCI (154mg, 0.8mmol), HOBT (108mg, 0.8mmol) and the mixture of diisopropylethylamine (0.23mL) in DMF (2mL) in stirred overnight at room temperature.Dilute this reaction mixture with ethyl acetate, successively use cold 1N HCl, saturated NaHCO 3With saturated NaCl solution washing.With MgSO 4Dry organic phase and vapourisation under reduced pressure solvent promptly get crude product.With the silica gel column chromatography purifying, with the mixture wash-out of ethyl acetate and heptane, promptly Morpholine-4-formic acid [(S)-3,3-two fluoro-1-((S)-1-hydroxymethyl -1-methyl-butyl formamyl)-4-phenyl-butyl]-acid amides(223mg, 75%).
Will Morpholine-4-formic acid [(S)-3,3-two fluoro-1-((S)-1-hydroxymethyl-1-methyl-butyl carbamyl Base)-4-phenyl-butyl]-acid amides(217mg) and the mixture of DMP (15%DCM solution, 2 equivalents) in DCM (5mL) in stirring at room 3 hours, and use saturated NaHCO 3In the hypo solution termination reaction.With this product of ethyl acetate extraction and with saturated NaCl solution washing.With anhydrous MgSO 4Dry organic phase and vapourisation under reduced pressure solvent.With the silica gel chromatography purifying, with ethyl acetate-heptane mixture wash-out, promptly Morpholine-4-formic acid [(S)-3,3-two fluoro-1-((S)-1-formyl radical-1-methyl- The butyl formamyl)-4-phenyl-butyl]-acid amides (83mg, 38%)
1H?NMR(CDCl 3)：δ9.3(s，1H)，7.2(m，5H)，7.0(s，1H)，5.0(d，J＝7Hz，1H)，4.64(dd，J＝13，7.3Hz，1H)，3.7(m，4H)，3.4(m，4H)，3.2(t，J＝16.5Hz，2H)，2.3(m，2H)，1.9(m，1H)，1.65(m，1H)，1.35(s，3H)，1.2(m，2H)，0.9(t，J＝7.3Hz，3H)；LC/MS：100％440.(M+1)。
Embodiment 20
Perhydro-1,4-oxygen azepine -4-formic acid (S)-1-[(S)-and 1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-difluoro butyl }-acid amides
To (S)-4,4-two fluoro-2-[(perhydros-1,4-oxygen azepine -4-carbonyl)-amino]-valeric acid (97mg, 0.35mmol), (S)-2-amino-1-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-Ding-1-alcohol hydrochloride (83mg, 0.36mmol) and diisopropylethylamine (121 μ L, 0.70mmol) mixture in dry methylene chloride (12mL) adds 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (66mg, 0.35mmol) and the I-hydroxybenzotriazole hydrate (47mg, 0.35mmol).This mixture in stirring at room 16 hours, is used methylene dichloride (20mL) dilution and then successively with rare HCl (30mL), saturated NaHCO 3(30mL) washing.Dry organic layer (Na 2SO 4) and concentrate in a vacuum.
Resistates through the 12g silica gel purification, is used ethyl acetate: heptane (gradient 50-100%) wash-out, promptly Perhydro-1,4-oxygen azepine -4-formic acid ((S)-1-{ (S)-1-[(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-hydroxyl Methyl]-the propyl group formamyl }-3,3-difluoro butyl)-acid amides(120mg, 75%) is flint glass shape solid.LC/MS?100％460(M+H)。
At N 2In the atmosphere; with DMP (143mg; 0.34mmol) adding perhydro-1; 4-oxygen azepine -4-formic acid ((S)-1-{ (S)-1-[(3-cyclopropyl-1; 2; 4-oxadiazole-5-yl)-hydroxymethyl]-the propyl group formamyl }-3,3-difluoro butyl)-(110mg is in the solution of 0.24mmoD in dry methylene chloride (20mL) for acid amides.This reactant in stirring at room 2 hours, is added methylene dichloride (20mL) then.Use Na 2S 2O 3(0.26M, 2mL) solution termination reaction, and use saturated NaHCO 3(20mL) washing.With methylene dichloride (2 * 30mL) aqueous layer extracted.With Na 2SO 4Dry organic layer also concentrates in a vacuum.Through 12g silica gel purification resistates, use ethyl acetate: heptane (gradient 50-100%) wash-out, promptly Perhydro-1,4- Oxygen azepine -4-formic acid (S)-1-[(S)-the amino first of 1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group Acyl group]-3,3-difluoro butyl }-acid amides(82mg, 75%) is white solid.
1H?NMR(CDCl 3)δ7.52(d，6.2H)，5.28(m，1H)，5.05(d，J＝7Hz，1H)，4.66(m，1H)，3.78(m，4H)，3.59(m，4H)，2.42(m，2H)，2.23(m，1H)，2.07(m，1H)，1.98(m，1H)，1.85(m，1H)，1.69(t，J＝18.8Hz，3H)，1.15(m，4H)，0.98(t，J＝7.5Hz，3H)；LC/MS：97％458(M+H)。
Embodiment 21
Perhydro-1,4-oxygen azepine -4-formic acid (S)-1-[(S)-and 1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides
Figure A20048003891200911
Carrying out, but use (S)-4,4-two fluoro-2-{ (perhydro-1,4-oxygen azepine -4-carbonyl)-amino with the foregoing description 20 similar modes }-enanthic acid and (S)-2-amino-1-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-Ding-1-alcohol hydrochloride, promptly make Perhydro-1,4-oxygen azepine -4-formic acid (S)-1-[(S)-1-(3-cyclopropyl -1,2,4-oxadiazole-5-carbonyl)-the propyl group formamyl]-3,3-difluoro hexyl }-acid amides(98mg, 65%) is white solid.
1H NMR (CDCl 3) δ 7.6 (d, J=7.5Hz, 1H), 5.25 (m, 1H), 5.10 (d, J=7.5Hz, 1H), 4.65 (dd, J=14, J=7.5Hz, 1H), 3.75 (m, 6H), 3.55 (m, 4H), 2.4 (m, 2H), 2.2 (m, 2H), 1.95 (m, 1H), 1.8 (m, 3H), 1.55 (m, 2H), 1.10 (m, 4H), 0.95 (t, J=7.5Hz, 6H); LC/MS:70%486 (M+1) and 30%504 (M+1+H2O).
Embodiment 22
Morpholine-4-formic acid (S)-1-[(S)-and 1-(3-sec.-propyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides
Figure A20048003891200921
Carrying out, but use with the foregoing description 20 similar modes (S)-4,4-two fluoro-2-[(morpholine-4- Carbonyl)-amino]-enanthic acid(S)-and 2-amino-1-(3-sec.-propyl-1,2,4-oxadiazole-5-yl)-Ding-1-alcohol, promptly make Morpholine-4-formic acid (S)-1-[(S)-the amino first of 1-(3-sec.-propyl-1,2,4-oxadiazole-5-carbonyl)-propyl group Acyl group]-3,3-difluoro hexyl }-acid amides(122mg, 71%) is white solid.
1H NMR (CDCl 3) δ 7.5 (d, J=7.0Hz, 1H), 5.3 (m, 1H), 5.25 (d, J=7.0Hz, 1H), 4.65 (dd, J=13,7.0Hz, 1H), 3.7 (m, 4H), 3.4 (m, 4H), 3.2 (m, 1H), 2.35 (m, 2H), 2.1 (m, 1H), 1.8 (m, 3H), 1.55 (m, 2H), 1.40 (d, J=7Hz, 6H), 0.9 (t, J=7.0Hz, 6H); LC/MS:72%474 (M+1) and 28%492 (M+1+H 2O).
Embodiment 23
Morpholine-4-formic acid (S)-1-[(S)-and 1-(the 5-tertiary butyl-1,2,4-oxadiazole-3-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides
Figure A20048003891200931
Use (S)-2-amino-1-(5-tertiary butyl-1 in succession, 2,4-oxadiazole-3-yl)-and Ding-1-alcohol (240mg, 1.13mmol), O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (226mg, 0.59mmol) and diisopropylethylamine (0.104mL 0.60mmol) handles (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls)-amino]-enanthic acid (175mg, 0.60mmol) solution in dimethyl formamide (6mL).With this reactant in stirred overnight at room temperature.Evaporating solvent under condition of high vacuum degree.Resistates is dissolved in ethyl acetate and successively uses 1N hydrochloric acid, the saturated bicarbonate aqueous solution and water washing, with Na 2SO 4Dry also vapourisation under reduced pressure solvent.Through silica gel (10g post) purification of crude thing, use the mixture wash-out of ethyl acetate and heptane (2: 1), promptly with flash chromatography Morpholine-4-formic acid ((S)-1-{ (the S)-1-[(5-tertiary butyl -1,2,4-oxadiazole-3-yl)-hydroxymethyl]-propyl group formamyl-3,3-difluoro hexyl)-acid amides, be brown oil (60mg).MS：490(M+H)。
With DMP (59mg; 0.139mmol) processing morpholine-4-formic acid ((S)-1-{ (the S)-1-[(5-tertiary butyl-1; 2; 4-oxadiazole-3-yl)-hydroxymethyl]-the propyl group formamyl }-3; 3-difluoro hexyl)-acid amides (57mg; 0.117mmol) solution in methylene dichloride (3mL), and in stirring at room 90min.Successively use Na 2S 2O 3The aqueous solution (0.26M), the saturated bicarbonate aqueous solution and this reaction mixture of water washing are with Na 2SO 4Dry also vapourisation under reduced pressure solvent.With the purified by flash chromatography resistates, with the mixture wash-out of ethyl acetate and heptane (1: 1), promptly get morpholine-4-formic acid (S)-1-[(S)-1-(the 5-tertiary butyl-1; 2; 4-oxadiazole-3-carbonyl)-and the propyl group formamyl]-3,3-difluoro hexyl }-acid amides, be pale solid (41mg).MS：488(M+H)。
Embodiment 24
Morpholine-4-formic acid (S)-and 1-[1-(the 5-tertiary butyl-1,2,4-oxadiazole-3-carbonyl)-propyl group formamyl]-3,3-two fluoro-4-phenyl-butyl }-acid amides
Carrying out, but use (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls with the foregoing description 23 similar modes)-amino]-5-phenylpentanoic acid and (S)-2-amino-1-(the 5-tertiary butyl-1,2,4-oxadiazole-3-yl)-Ding-1-alcohol, promptly make Morpholine-4-formic acid (S)-1-[1-(the 5-tertiary butyl-1,2,4-oxadiazole-3-carbonyl)-propyl group amino Formyl radical]-3,3-two fluoro-4-phenyl-butyl }-acid amides, be 7: 3 non-enantiomer mixtures.
1H?NMR(CDCl 3)δ：7.36-7.19(m，5H)，7.15(d，J＝7.1Hz，1H)，5.31(m，1H)，5.03?&?4.96(2xd，J＝7Hz，1H)，4.68(m，1H)，3.76-3.59(m，4H)，3.45-3.26(m，4H)，3.18(t，J＝16.8Hz，2H)，2.52-2.18(m，2H)，2.17-1.94(m，1H)，1.88-1.70(m，1H)，1.47(s，9H)，0.93(t，J＝7.4Hz，3H)。MS：536(M+H)。
Embodiment 25
Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{ (S)-1-[5-(4-fluoro-phenyl)-1,2,4-oxadiazole-3-carbonyl]-the propyl group formamyl }-butyl)-acid amides
Figure A20048003891200942
Carrying out, but use (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls with the foregoing description 23 similar modes)-amino]-valeric acid and (S)-2-amino-1-[5-(4-fluoro-phenyl)-1,2,4-oxadiazole-3-yl]-Ding-1-alcohol, promptly make Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{ (S)-1-[5-(4-fluoro-phenyl)-1,2,4-oxadiazole-3-carbonyl Base]-the propyl group formamyl }-butyl)-acid amides.
1H?NMR(CDCl 3)δ：8.21(m，2H)，7.31(d，J＝6.8Hz，1H)，7.30-7.20(m，2H)，5.38(m，1H)，5.07(d，J＝6.8Hz，1H)，4.63(m，1H)，3.75-3.64(m，4H)，3.44-3.33(m，4H)，2.58-2.28(m，2H)，2.22-2.04(m，1H)，1.96-1.79(m，1H)，1.66(t，J＝18.8Hz，3H)，0.97(t，J＝7.4Hz，3H)。MS：498(M+H)。
Embodiment 26
Morpholine-4-formic acid (S)-and 1-[1-(5-cyclopropyl-1,2,4-oxadiazole-3-carbonyl)-propyl group formamyl]-3,3-two fluoro-4-phenyl-butyl }-acid amides
To carry out with the foregoing description 23 similar modes; but use (S)-4; 4-two fluoro-2-[(morpholine-4-carbonyls)-amino]-5-phenylpentanoic acid and (S)-2-amino-1-(5-cyclopropyl-1; 2,4-oxadiazole-3-yl)-Ding-1-alcohol, promptly make morpholine-4-formic acid (S)-1-[1-(5-cyclopropyl-1; 2; 4-oxadiazole-3-carbonyl)-and the propyl group formamyl]-3,3-two fluoro-4-phenyl-butyl }-acid amides, be 3: 1 non-enantiomer mixtures.
1H?NMR(CDCl 3)δ：7.36-7.20(m，5H)，7.14(d，J＝7.1Hz，1H)，5.26(m，1H)，5.02?&?4.96(2xd，J＝7Hz，1H)，4.70(m，1H)，3.73-3.61(m，4H)，3.43-3.28(m，4H)，3.18(t，J＝16.5Hz，2H)，2.48-2.21(m，3H)，2.14-1.98(m，1H)，1.85-1.70(m，1H)，1.38-1.21(m，4H)，0.91(t，J＝7.5Hz，3H)。MS：520(M+H)。
Embodiment 27
Perhydro-1,4-oxygen azepine -4-formic acid (S))-1-[1-(5-cyclopropyl-1,2,4-oxadiazole-3-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides
Figure A20048003891200952
Carrying out, but use (S)-4,4-two fluoro-2-[(perhydros-1,4-oxygen azepine -4-carbonyl with the foregoing description 23 similar modes)-amino]-enanthic acid and (S)-2-amino-1-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-Ding-1-alcohol, promptly make Perhydro-1,4-oxygen azepine -4-formic acid (S)-1-[1-(5-cyclopropyl-1,2,4-oxadiazole -3-carbonyl)-and the propyl group formamyl]-3,3-difluoro hexyl }-acid amides, be 5: 1 non-enantiomer mixtures.
1H?NMR(CDCl 3)：7.44?&?7.39(2xd，J＝7.3Hz，1H)，5.30(m，1H)，5.05?&4.98(2xd，J＝6.5Hz，1H)，4.63(m，1H)，3.79-3.73(m，4H)，3.59-3.53(m，4H)，2.47-2.23(m，3H)，2.15-1.76(m，6H)，1.57-1.43(m，2H)，1.38-1.26(m，4H)，0.95(t，J＝7.3Hz，3H)，0.93(t，J＝7.2Hz，3H)。MS：486(M+H)。
Embodiment 28
Perhydro-1,4-oxygen azepine -4-formic acid [(S)-and 1-(cyano methyl-formamyl)-3,3-difluoro hexyl]-acid amides
Figure A20048003891200961
With polystyrene bonded carbodiimide (570mg, 0.73mmol) and (S)-4,4-two fluoro-2-[(perhydros-1,4-oxygen azepine -4-carbonyl)-amino]-suspension of enanthic acid (135mg) in DCM (10mL) stirs 10min.Add HOBT (60mg), restir 10min.Add aminoacetonitriles hydrochloride (34mg) and the suspension of triethylamine (52 μ L) in DCM (5ml), and in stirred overnight at room temperature.Add PS-Pehanorm (493mg) and in stirring at room 2h 30min.After the filtration, dilute filtrate with DCM, wash with water, vapourisation under reduced pressure and with the column chromatography purifying is with the mixture wash-out of ethyl acetate and heptane, promptly Perhydro-1, and 4-oxygen azepine -4-formic acid [(S)-1-(cyano methyl-carbamyl Base)-3,3-difluoro hexyl]-acid amides, be white solid.LCMS：100％347(M+H)。
Embodiment 29
Perhydro-1,4-oxygen azepine -4-formic acid [(S)-and 1-((S)-1-cyano group propyl group formamyl)-3,3-difluoro hexyl]-acid amides
Carrying out, but use 4,4-two fluoro-2-[([1,4 with the foregoing description 28 similar modes] oxaza heptane-4-carbonyl)-amino]-enanthic acid and (S)-2-aminobutyronitrile hydrochloride, promptly make Perhydro-1,4-oxygen nitrogen Assorted -4-formic acid [(S)-and 1-((S)-1-cyano group propyl group formamyl)-3,3-difluoro hexyl]-acid amidesLCMS：100％375(M+H)。
Embodiment 30
Morpholine-4-formic acid [(S)-and 1-(1-cyano group-cyclopropyl formamyl)-3,3-difluoro hexyl]-acid amides
By (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls)-amino]-enanthic acidMake with the hydrochloride reaction of the amino cyclopropyl nitrile of 1-, use TOTU as coupling agent, diisopropylethylamine is as alkali.LCMS：359(M+H)。
Embodiment 31
The cathepsin S test
The test compound solution of the various concentration of preparation in 10 μ L dimethyl sulfoxide (DMSO) (DMSO), (40 μ L contain: MES, 50mM (pH6.5) for the test damping fluid in dilution then; EDTA, 2.5mM; And NaCl, 100mM, 0.5mM DTT, 0.01%triton X-100).
Human cathepsin S (final concentration in culture hole is 1.74nM) is added this diluent.This testing liquid is mixed 5-10 second on the shaking culture plate, cover the back and cultivate 30min in envrionment temperature.Z-Val-Val-Arg-AMC (final concentration in culture hole is 0.08mM) is added this testing liquid, follow the tracks of hydrolysis with spectrophotometry (in λ 460nm) then and reach 5min.The mathematical model of utilizing standard is from enzyme process curve calculation apparent inhibition constant (K i).
Embodiment 32
Cathepsin B's test
The test compound solution of the various concentration of preparation in 10 μ L dimethyl sulfoxide (DMSO) (DMSO), dilution (contains: MES 50mM (pH 6) for the test damping fluid then; 2.5mM EDTA, 2%DMSO and dithiothreitol (DTT) (DTT), 2.5mM).
Human cathepsin B (final concentration is 0.3ng/ μ l) is added this diluent.This testing liquid is mixed 5-10 second on the shaking culture plate, cover the back and cultivate 30min in envrionment temperature.Z-FR-pNa (final concentration is 100 μ M) is added this testing liquid, follow the tracks of hydrolysis with spectrophotometry (in λ 405nm) then and reach 60min.The mathematical model of utilizing standard is from enzyme process curve calculation apparent inhibition constant (K i).
Embodiment 33
The cathepsin K test
The test compound solution of the various concentration of preparation in 10 μ L dimethyl sulfoxide (DMSO) (DMSO), (40 μ L contain: MES, 50mM (pH 5.5) for the test damping fluid in dilution then; EDTA, 2.5mM; And DDT, 2.5mM).Human cathepsin K (0.0906pMoles, 25 μ L test damping fluid) is added this diluent.This testing liquid is mixed 5-10 second on the shaking culture plate, cover the back and cultivate 30min in envrionment temperature.Z-Phe-Arg-AMC (4nMoles, 25 μ L test damping fluid) is added this testing liquid, follow the tracks of hydrolysis with spectrophotometry (λ 460nm) then and reach 5min.The mathematical model of utilizing standard is from enzyme process curve calculation apparent inhibition constant (K i).
Embodiment 34
Cathepsin L analyzes
The test compound solution of the various concentration of preparation in 10 μ L dimethyl sulfoxide (DMSO) (DMSO), (40 μ L contain: MES, 50mM (pH 6) for the test damping fluid in dilution then; EDTA, 2.5mM; And DTT, 2.5mM).Human cathepsin L (10 μ L, 0.2ng/ μ L, final concentration are 0.02ng/ μ l) is added this diluent.This testing liquid is mixed 5-10 second on the shaking culture plate, cover the back and cultivate 30min in envrionment temperature.Z-Phe-Arg-AMC (0.1mM, 10 μ L, final concentration are 10 μ M) is added this testing liquid, follow the tracks of hydrolysis with spectrophotometry (λ 460nm) then and reach 30min.The mathematical model of utilizing standard is from enzyme process curve calculation apparent inhibition constant (K i).
Tested compound of the present invention according to above-mentioned proteolytic enzyme inhibition test method, observed it and show that the selectivity cathepsin S suppresses active.The compounds of this invention is with respect to the apparent inhibition constant (K of cathepsin S i) about 10 -10M is to about 10 -7In the scope of M.
Embodiment 35
The typical medicaments preparation that contains formula (I) compound:
Oral preparations
The compound 10-100mg of formula I
Citric acid monohydrate 105mg
Sodium hydroxide 18mg
Seasonings
Water is in right amount to 100mL
Iv formulation
The compound 0.1-10mg of formula I
Five equilibrium behind the glucose monohydrate constant volume
Citric acid monohydrate 1.05mg
Sodium hydroxide 0.18mg
Water for injection is in right amount to 1.0mL
Tablet formulation
The compound 1% of formula I
Microcrystalline Cellulose 73%
Stearic acid 25%
Colloidal silica 1%
Though narrated and pointed out the novel feature that the present invention is basic already, shown in its preferred embodiment, but should be appreciated that, can carry out various deletions, replacement and change to the pharmaceutical composition of being demonstrated and the form and the details of method by those present technique field skilled staff, only otherwise deviating from spirit of the present invention gets final product.For example, clear and definite is intended that, and carries out same in fact function, replaces and/or method steps with the chemical group that reaches equifinality in same in fact mode, all belongs within the scope of the invention.
The invention is not restricted to the above-mentioned embodiment that only proposes, but these embodiment can revise in every way in the defined protection domain of claims as embodiment.
Claims
(according to the modification of the 19th of treaty)
3. the compound that has formula (I) structure:
Figure A20048003891201011
Wherein
A is
X 1Be methylene radical, ethylidene or key;
X 2Be CN, CHO, C (O) R 6, C (O) C (O) NR 7R 7, C (O) C (O) NR 7R 8, C (O) C (O) R 13, C (O) C (O) OR 13, C (O) CH 2X 3R 13
X 3Be selected from O, S (O) n, CO, CONH, NHCO, NHSO 2And SO 2NH;
X 4Be CH (R 12) or CH (R 12)-CH 2
X 5Be methylene radical, ethylidene, propylidene or key;
X 6Be key or (C 1-2) alkylene;
R 1Be R 13C (O)-, R 13S (O) 2-, R 13OC (O)-, R 8R 7NC (O)-, R 8R 7NS (O) 2-; R 13S (O) 2NC (O)-or R 13C (O) NS (O) 2-;
R 2Be selected from hydrogen, (C 1-6) alkyl, (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, assorted (C 5-12) cyclic hydrocarbon radical (C 0-6) R wherein 6Be alternatively by (C 1-9) alkyl, (C 3-12) cyclic hydrocarbon radical, (C 6-12) aryl or assorted (C 5-13) assorted (C that replaces of aryl 5-13) aryl.
8. the compound of claim 3, wherein A is
Figure A20048003891201021
9. the compound of claim 8, wherein X 5It is propylidene.
10. claim 8 or 9 compound, wherein R 11Be-C (O) OR 13Or-S (O) 2R 13, R wherein 13Be alkyl or (C 6-12) aryl.
11. the compound of any one, wherein R among the claim 3-10 1Be (i) R 13C (O)-, R wherein 13Be assorted (C 5-12) cyclic hydrocarbon radical; (ii) R 13OC (O)-, R wherein 13Be (C 6-12) aryl (C 1-6) alkyl; (iii) (C 1-9) alkyl; Or (iv) assorted (C 5-12) cyclic hydrocarbon radical.
12. the compound of any one, wherein R among the claim 3-11 2Be H.
13. the compound of any one, wherein R among the claim 3-12 5Be (C 1-9) alkyl or (C 6-12) aryl (C 1-6) alkyl.
14. formula (Ia) compound:
Figure A20048003891201022
R wherein 1, R 3, R 4And R 5As indicated above, and their corresponding N-oxide compounds, their prodrug, their protected derivative, their independent isomer and isomer mixture; And the pharmacy acceptable salt and the solvate (for example hydrate) of this class formula (Ia) compound and their N-oxide compound, their prodrug, their protected derivative, their independent isomer and isomer mixture.
15. formula (Ib) compound:
27. the compound of any one, wherein R in the claim 16,18,19 and 24 5Be (C 1-9) alkyl or (C 6-12) aryl (C 1-6) alkyl.
28. the compound of claim 25, wherein R 5Be CH 3CH 2CH 2Or CH 3CH 2Or CH 3Or
Figure A20048003891201031
29. claim 16,18,19,24,27 and 28 compound, wherein R 6Be alternatively by (C 1-9) alkyl, (C 3-12) cyclic hydrocarbon radical, (C 6-12) aryl or assorted (C 5-13) assorted (C that replaces of aryl 5-13) aryl.
30. the compound of claim 29, wherein R 6Be benzoxazolyl, oxadiazole base, isoxazolyl ， Huo oxazolyl, replaced by one or more aryl or hydrocarbyl substituent alternatively separately.
31. the compound of claim 30, wherein R 6It is benzoxazole-2-base, the 5-tertiary butyl-[1,2,4] oxadiazole-3-base, 3-cyclopropyl-1,2,4-oxadiazole-5-base, 5-cyclopropyl-1,2,4-oxadiazole-3-base, 5-cyclopropyl-1,3,4-oxadiazole-2-base, 5-ethyl-1,3,4-oxadiazole-2-base, 5-(4-fluoro-phenyl)-1,2,4-oxadiazole-3-base 5-sec.-propyl-isoxazole-3-base 5-(5-methyl-isoxazole-3-yl)-oxazoles-2-base 5-(5-methyl-thiophene-2-yl)-oxazoles-2-base oxazole-2-base, 3-phenyl-1,2,4-oxadiazole-5-base, 5-phenyl-1,2,4-oxadiazole-3-base, 5-thiophene-2-base-oxazoles-2-base, or 5-(4-Trifluoromethoxyphen-l)-1,3,4-oxadiazole-2-base.
32. the compound of claim 31, wherein R 6Be benzoxazole-2-base, 3-cyclopropyl-1,2,4-oxadiazole-5-Ji, oxazole-2-base, or 5-cyclopropyl-1,2,4-oxadiazole-3-base.
33. the compound of claim 17, wherein R 11Be-C (O) OR 13Or-S (O) 2R 13, R wherein 13Be alkyl or (C 6-12) aryl.
34. the compound of claim 28, wherein R 11Be-C (O) OC (CH 3) 3Or
Figure A20048003891201032
35. the compound of claim 3 is selected from down the group compound:
Morpholine-4-formic acid (S)-1-[(S)-and 1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides;
Morpholine-4-formic acid (S)-1-[(S)-and 1-(5-cyclopropyl-1,3,4-oxadiazole-2-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides;
Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{ (S)-1-[5-(4-Trifluoromethoxyphen-l)-1,3,4-oxadiazole-2-carbonyl]-the propyl group formamyl }-hexyl)-acid amides;
Morpholine-4-formic acid (S)-1-[(S)-and 1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-two fluoro-4-phenyl-butyl }-acid amides;
Morpholine-4-formic acid 1-[1-(3-cyclopropyl-[1,2,4] oxadiazole-5-carbonyl)-propyl group formamyl] and-3,3-two fluoro-5-methyl-hexyls }-acid amides;
Morpholine-4-formic acid (S)-1-[(S)-and 1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-difluoro butyl }-acid amides;
Morpholine-4-formic acid (S)-3,3-two fluoro-1-[(S)-1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-butyl }-acid amides;
Morpholine-4-formic acid (S)-3,3-two fluoro-1-[(S)-1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl group formamyl]-butyl }-acid amides;
Morpholine-4-formic acid 1-[1-(5-cyclopropyl-[1,3,4] oxadiazole-2-carbonyl)-propyl group formamyl] and-3,3-two fluoro-4-phenyl-butyl }-acid amides;
Morpholine-4-formic acid 3,3-two fluoro-1-[1-(the different propyl group isoxazole of 5--3-carbonyl)-propyl group formamyl]-hexyl }-acid amides;
Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{1-[5-(5-methyl-isoxazole-3-yl)-oxazole-2-carbonyl]-the propyl group formamyl }-hexyl)-acid amides;
Morpholine-4-formic acid (S)-3,3-two fluoro-1-[(S)-1-(oxazole-2-carbonyl)-propyl group formamyl]-4-phenyl-butyl }-acid amides;
Morpholine-4-formic acid (S)-3,3-two fluoro-4-phenyl-1-[(S)-1-(5-thiophene-2-base oxazole-2-carbonyl)-propyl group formamyl]-butyl }-acid amides;
Morpholine-4-formic acid (S)-1-[(S)-and 1-(benzoxazole-2-carbonyl)-butyl formamyl]-3,3-two fluoro-4-phenyl-butyl }-acid amides;
Morpholine-4-formic acid [1-(2-benzoxazole-2-base-1-methoxymethyl-2-oxoethyl formamyl)-3,3-two fluoro-4-phenyl-butyl]-acid amides;
Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{1-[5-(4-fluoro-phenyl)-1,2,4-oxadiazole-3-carbonyl]-the propyl group formamyl }-butyl)-acid amides;
Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{ (R)-1-[5-(4-fluoro-phenyl)-1,2,4-oxadiazole-3-carbonyl]-the propyl group formamyl }-butyl)-acid amides;
Morpholine-4-formic acid (S)-1-[(S)-1-(benzoxazole-2-carbonyl)-the propyl group formamyl]-3,3-difluoro butyl }-acid amides;
Morpholine-4-formic acid [(S)-and 1-(cyano methyl-formamyl)-3,3-difluoro hexyl]-acid amides;
Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{ (R)-1-[5-(5-thiotolene-2-yl)-oxazole-2-carbonyl]-the propyl group formamyl }-hexyl)-acid amides;
Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{ (S)-1-[5-(5-thiotolene-2-yl)-oxazole-2-carbonyl]-the propyl group formamyl }-hexyl)-acid amides;
And their corresponding N-oxide compounds, their prodrug, their protected derivative, their independent isomer and isomer mixture; And the pharmacy acceptable salt and the solvate (for example hydrate) of this class formula (Ia) compound and their N-oxide compound, their prodrug, their protected derivative, their independent isomer and isomer mixture.
36. contain the compound of claim 3 and the pharmaceutical composition of pharmaceutical acceptable excipient.
37. suppress the method for patient tissue proteolytic enzyme S, wherein the increase of cathepsin S enzymic activity promotes described patient's pathology illness, this method is to the compound of the claim 3 of described patient's administering therapeutic significant quantity.
38. the compound of claim 3 is used for the treatment of purposes in patient's the medicine in preparation, described patient suffers from or easily suffers from the illness that can improve by this compound of using as cathepsin S inhibitor.
39. the compound of claim 35 is used for the treatment of purposes in patient's the medicine in preparation, described patient suffers from or easily suffers from the illness that can improve by this compound of using as cathepsin S inhibitor.
40. the compound of claim 3 is used for the treatment of purposes in patient's the medicine in preparation, described patient suffers from or easily suffers from the illness that can improve by this compound of using as cathepsin B inhibitors.Method, it comprises compound from the claim 3 of inhibition of histone enzyme S significant quantity to the patient that needs are arranged that use.
52. inhibition of histone enzyme S level rising patient's the active method of cathepsin S optionally, it comprises compound from the claim 35 of inhibition of histone enzyme S significant quantity to the patient that needs are arranged that use.
53. the arthritic method of treatment mammalian bone comprises the compound to the claim 42 of described administration significant quantity.
54. the compound of any one, wherein R in the claim 3 to 10,12 to 18 or 20 to 30 1Be
Figure A20048003891201061
55. the compound of claim 3 is selected from down group:
Perhydro-1,4-oxygen azepine -4-formic acid (S)-1-[(S)-and 1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-difluoro butyl }-acid amides;
Perhydro-1,4-oxygen azepine -4-formic acid (S)-1-[(S)-and 1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides;
Morpholine-4-formic acid (S)-1-[(S)-and 1-(3-sec.-propyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides;
Morpholine-4-formic acid (S)-1-[(S)-and 1-(the 5-tertiary butyl-1,2,4-oxadiazole-3-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides;
Perhydro-1,4-oxygen azepine -4-formic acid (S)-and 1-[1-(5-cyclopropyl-1,2,4-oxadiazole-3-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides;
Perhydro-1,4-oxygen azepine -4-formic acid [(S)-and 1-(cyano methyl-formamyl)-3,3-difluoro hexyl]-acid amides;
Perhydro-1,4-oxygen azepine -4-formic acid [(S)-and 1-((S)-1-cyano group propyl group formamyl)-3,3-difluoro hexyl]-acid amides; With
Morpholine-4-formic acid [(S)-and 1-(1-cyano group-cyclopropyl formamyl)-3,3-difluoro hexyl]-acid amides.
57. inhibition of histone enzyme K level rising patient's the active method of cathepsin K optionally, it comprises compound from the claim 55 of inhibition of histone enzyme K significant quantity to the patient that needs are arranged that use.
58. inhibition of histone enzyme S level rising patient's the active method of cathepsin S optionally, it comprises compound from the claim 55 of inhibition of histone enzyme S significant quantity to the patient that needs are arranged that use.
59. inhibition of histone enzyme B level rising patient's the active method of cathepsin B optionally, it comprises compound from the claim 55 of inhibition of histone enzyme B significant quantity to the patient that needs are arranged that use.
60. the arthritic method of treatment mammalian bone comprises the compound to the claim 55 of described administration significant quantity.
61. inhibition of histone enzyme B level rising patient's the active method of cathepsin B optionally, it comprises compound from the claim 3 of inhibition of histone enzyme B significant quantity to the patient that needs are arranged that use.
62. inhibition of histone enzyme B level rising patient's the active method of cathepsin B optionally, it comprises compound from the claim 42 of inhibition of histone enzyme B significant quantity to the patient that needs are arranged that use.

Claims (62)

1. the compound that has formula II backbone structure:
Figure A2004800389120002C1
X wherein 1Be methylene radical, ethylidene or key, and sub 1-sub 4It is general substituting group.
2. the compound of claim 1, it has the backbone structure that is selected from formula III, IV and V:
Figure A2004800389120002C2
X wherein 1Be methylene radical, ethylidene or key, and sub 1-sub 8It is general substituting group.
3. the compound that has formula (I) structure:
Wherein
A is
X 1Be methylene radical, ethylidene or key;
X 2Be CN, CHO, C (O) R 6, C (O) C (O) NR 7R 7, C (O) C (O) NR 7R 8, C (O) C (O) R 13, C (O) C (O) OR 13, C (O) CH 2X 3R 13
X 3Be selected from O, S (O) n, CO, CONH, NHCO, NHSO 2And SO 2NH;
X 4Be CH (R 12) or CH (R 12)-CH 2
X 5Be methylene radical, ethylidene, propylidene or key;
X 6Be key or (C 1-2) alkylene;
R 1Be H, R 13C (O)-, R 13S (O) 2-, R 13OC (O)-, R 8R 7NC (O)-, R 8R 7NS (O) 2-; R 13S (O) 2NC (O)-or R 13C (O) NS (O) 2-; Or R 1Be selected from (C 1-9) alkyl, (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, assorted (C 5-12) cyclic hydrocarbon radical (C 0-6) alkyl, (C 6-12) aryl (C 0-6) alkyl and assorted (C 5-13) aryl (C 0-6) alkyl, each group is replaced by 1 to 5 group that is independently selected from down group alternatively: (C 1-4) alkyl, cyano group, halogen, halo (C 1-4) alkyl ,-X 6NR 9R 9,-X 6OR 9,-X 6SR 9,-X 6C (O) NR 9R 9,-X 6OC (O) NR 9R 9,-X 6C (O) OR 9,-X 6NC (O) OR 9,-X 6S (O) R 10,-X 6S (O) 2R 10With-X 6C (O) R 10
R 2Be selected from hydrogen, (C 1-6) alkyl, (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, assorted (C 5-12) cyclic hydrocarbon radical (C 0-6) alkyl, (C 6-12) aryl (C 0-6) alkyl or assorted (C 5-12) aryl (C 0-6) alkyl;
R 3Be selected from H, (C 1-6) alkyl, (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, assorted (C 5-12) cyclic hydrocarbon radical (C 0-6) alkyl, (C 6-12) aryl (C 0-6) alkyl or assorted (C 5-13) aryl (C 0-6) alkyl, replaced by 1 to 5 group that is independently selected from down group alternatively: (C 1-4) alkyl, cyano group, halogen, halo (C 1-4) alkyl ,-X 6NR 9R 9,-X 6OR 9,-X 6SR 9,-X 6C (O) NR 9R 9,-X 6OC (O) NR 9R 9,-X 6C (O) OR 9,-X 6NC (O) OR 9,-X 6S (O) R 10,-X 6S (O) 2R 10With-X 6C (O) R 10
R 4Be H or (C 1-6) alkyl; Or R 3And R 4With R 3And R 4The carbon atom that both all link to each other forms (C together 3-8) inferior cyclic hydrocarbon radical or (C 3-8) inferior heterocycle alkyl;
R 5Be H, F, or R 5Be (C 1-9) alkyl, (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, assorted (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, (C 6-12) aryl (C 0-6) alkyl, assorted (C 5-13) aryl (C 0-6) alkyl, replaced by 1 to 5 group that is independently selected from down group alternatively separately: (C 1-4) alkyl, cyano group, halogen, halo (C 1-4) alkyl ,-X 6NR 9R 9,-X 6OR 9,-X 6SR 9,-X 6C (O) NR 9R 9,-X 6OC (O) NR 9R 9,-X 6C (O) OR 9,-X 6NC (O) OR 9,-X 6S (O) R 10,-X 6S (O) 2R 10With-X 6C (O) R 10
R 6Be (C 6-12) aryl, assorted (C 5-13) aryl and halo (C 1-6) alkyl; R wherein 6Replaced by 1 to 5 group that is independently selected from down group alternatively: (C 1-9) alkyl, (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, assorted (C 5-12) cyclic hydrocarbon radical (C 0-6) alkyl, (C 6-12) aryl (C 0-6) alkyl, assorted (C 5-13) aryl (C 0-6) alkyl, cyano group, halogen, halo (C 1-6) alkyl ,-X 6NR 9R 9,-X 6OR 9,-X 6SR 9,-X 6C (O)-NR 9R 9,-X 6OC (O) NR 9R 9,-X 6C (O) OR 9,-X 6NC (O) OR 9,-X 6S (O) R 10,-X 6S (O) 2R 10With-X 6C (O) R 10
R 7Be H, (C 1-6) alkyl, (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, assorted (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, (C 6-12) aryl (C 0-6) alkyl, assorted (C 5-13) aryl (C 0-6) alkyl and halo (C 1-6) alkyl; R wherein 7Replaced by 1 to 5 group that is independently selected from down group alternatively: (C 1-4) alkyl, cyano group, halogen, halo (C 1-4) alkyl ,-X 6NR 9R 9,-X 6OR 9,-X 6SR 9,-X 6C (O) NR 9R 9,-X 6OC (O) NR 9R 9,-X 6C (O) OR 9,-X 6NC (O) OR 9,-X 6S (O) R 10,-X 6S (O) 2R 10With-X 6C (O) R 10
R 8Be selected from H, (C 1-6) alkyl, (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, assorted (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, (C 6-12) aryl (C 0-6) alkyl and assorted (C 5-13) aryl (C 0-6) alkyl, or R 7And R 8Form (C with the atom that links to each other 3-8) inferior cyclic hydrocarbon radical or (C 3-8) inferior heterocycle alkyl;
R 9Be hydrogen, (C independently when occurring at every turn 1-6) alkyl or halo (C 1-6) alkyl;
R 10Be (C 1-6) alkyl or halo (C 1-6) alkyl;
R 11Be selected from hydrogen, (C 1-9) alkyl, (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, assorted (C 5-12) cyclic hydrocarbon radical (C 0-6) alkyl, (C 6-12) aryl (C 0-6) alkyl, assorted (C 5-13) aryl (C 0-6) alkyl, (C 9-12) aryl bicyclic (C 0-3) alkyl, assorted (C 8-12)-aryl bicyclic (C 0-3) alkyl ,-C (O) R 13,-C (S) R 13,-S (O) 2R 13,-C (O) OR 13,-C (O) N (R 7) R 8,-C (S) N (R 7) R 8With-S (O) 2N (R 7) R 8
R 12Be H or C 1-6Alkyl is alternatively by amido, (C 6-12) aryl, assorted (C 5-12) aryl, assorted (C 5-12) cyclic hydrocarbon radical or hydroxyl replacement;
R 13Be (C 1-6) alkyl, (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, assorted (C 3-12) cyclic hydrocarbon radical (C 0-6) alkyl, (C 6-12) aryl (C 0-6) alkyl, assorted (C 5-13) aryl (C 0-6) alkyl and halo (C 1-6) alkyl; R wherein 13Replaced by 1 to 5 group that is independently selected from down group alternatively: (C 1-4) alkyl, cyano group, halogen, halo (C 1-4) alkyl ,-X 6NR 9R 9,-X 6OR 9,-X 6SR 9,-X 6C (O) NR 9R 9,-X 6OC (O) NR 9R 9,-X 6C (O) OR 9,-X 6NC (O) OR 9,-X 6S (O) R 10,-X 6S (O) 2R 10With-X 6C (O) R 10And
N is zero or integer 1 or 2;
And their corresponding N-oxide compounds, their prodrug, their protected derivative, their independent isomer and isomer mixture; And the pharmacy acceptable salt and the solvate (for example hydrate) of this class formula (Ia) compound and their N-oxide compound, their prodrug, their protected derivative, their independent isomer and isomer mixture.
4. the compound of claim 3, wherein A is
Figure A2004800389120005C1
5. the compound of claim 4, wherein R 3Be H, (C 6-12) aryl (C 2-6) alkyl or alternatively by-X 6OR 9(the C that replaces 1-6) alkyl, wherein X 6Be key and R 9Be (C 1-6) alkyl.
6. claim 4 or 5 compound, wherein R 4Be H or (C 1-6) alkyl.
7. the compound of any one, wherein X among the claim 4-6 2Be CHO, CN or C (O) R 6, R wherein 6Be alternatively by (C 1-9) alkyl, (C 3-12) cyclic hydrocarbon radical, (C 6-12) aryl or assorted (C 5-13) assorted (C that replaces of aryl 5-13) aryl.
8. the compound of claim 3, wherein A is
Figure A2004800389120006C1
9. the compound of claim 8, wherein X 5It is propylidene.
10. claim 8 or 9 compound, wherein R 11Be-C (O) OR 13Or-S (O) 2R 13, R wherein 13Be alkyl or (C 6-12) aryl.
11. the compound of any one, wherein R among the claim 2-10 1Be (i) R 13C (O)-, R wherein 13Be assorted (C 5-12) cyclic hydrocarbon radical; (ii) R 13OC (O)-, R wherein 13Be (C 6-12) aryl (C 1-6) alkyl; (iii) (C 1-9) alkyl; Or (iv) assorted (C 5-12) cyclic hydrocarbon radical.
12. the compound of any one, wherein R among the claim 2-11 2Be H.
13. the compound of any one, wherein R among the claim 2-12 5Be (C 1-9) alkyl or (C 6-12) aryl (C 1-6) alkyl.
14. formula (Ia) compound:
R wherein 1, R 3, R 4And R 5As indicated above, and their corresponding N-oxide compounds, their prodrug, their protected derivative, their independent isomer and isomer mixture; And the pharmacy acceptable salt and the solvate (for example hydrate) of this class formula (Ia) compound and their N-oxide compound, their prodrug, their protected derivative, their independent isomer and isomer mixture.
15. formula (Ib) compound:
R wherein 1, R 3, R 4And R 5As indicated above, and their corresponding N-oxide compounds, their prodrug, their protected derivative, their independent isomer and isomer mixture; And the pharmacy acceptable salt and the solvate (for example hydrate) of this class formula (Ib) compound and their N-oxide compound, their prodrug, their protected derivative, their independent isomer and isomer mixture.
16. formula (Ic) compound:
Figure A2004800389120007C2
R wherein 1, R 3, R 4, R 5And R 6As indicated above, and their corresponding N-oxide compounds, their prodrug, their protected derivative, their independent isomer and isomer mixture; And the pharmacy acceptable salt and the solvate (for example hydrate) of this class formula (Ic) compound and their N-oxide compound, their prodrug, their protected derivative, their independent isomer and isomer mixture.
17. formula (Id) compound:
R wherein 1, R 5, R 11And X 5As indicated above, and their corresponding N-oxide compounds, their prodrug, their protected derivative, their independent isomer and isomer mixture; And the pharmacy acceptable salt and the solvate (for example hydrate) of this class formula (Id) compound and their N-oxide compound, their prodrug, their protected derivative, their independent isomer and isomer mixture.
18. the compound of any one, wherein R among the claim 14-17 1Be R 13C (O)-, R wherein 13Be assorted (C 5-12) cyclic hydrocarbon radical.
19. the compound of claim 18, wherein R 1Be
Figure A2004800389120008C1
20. the compound of any one, wherein R in the claim 14,15,18 or 19 3Be H, (C 6-12) aryl (C 1-6) alkyl or (C 1-6) alkyl.
21. the compound of claim 20, wherein R 3Be H,
Figure A2004800389120008C2
CH 3CH 2CH 2-.
22. the compound of any one, wherein R in the claim 16,18 or 19 3Be alternatively by-X 6OR 9(the C that replaces 1-6) alkyl, wherein X 6Be key, R 9Be (C 1-6) alkyl.
23. the compound of claim 22, wherein R 3Be CH 3-CH 2-, CH 3-CH 2-CH 2-or CH 3-O-CH 2-.
24. the compound of any one, wherein R among claim 14-16 and the 18-23 4Be H or methyl.
25. the compound of any one, wherein R among claim 14,15,17, the 18-21 and 24 5Be (C 6-12) aryl (C 1-6) alkyl.
26. the compound of claim 25, wherein R 5Be
27. the compound of any one, wherein R in the claim 16,18,19 and 24 5Be (C 1-9) alkyl or (C 6-12) aryl (C 1-6) alkyl.
28. the compound of claim 25, wherein R 5Be CH 3CH 2CH 2Or CH 3CH 2Or CH 3
Figure A2004800389120009C1
29. claim 16,18,19,24,27 and 28 compound, wherein R 6Be alternatively by (C 1-9) alkyl, (C 3-12) cyclic hydrocarbon radical, (C 6-12) aryl or assorted (C 5-13) assorted (C that replaces of aryl 5-13) aryl.
30. the compound of claim 29, wherein R 6Be benzoxazolyl, oxadiazole base, isoxazolyl ， Huo oxazolyl, replaced by one or more aryl or hydrocarbyl substituent alternatively separately.
31. the compound of claim 30, wherein R 6It is benzoxazole-2-base, the 5-tertiary butyl-[1,2,4] oxadiazole-3-base, 3-cyclopropyl-1,2,4-oxadiazole-5-base, 5-cyclopropyl-1,2,4-oxadiazole-3-base, 5-cyclopropyl-1,3,4-oxadiazole-2-base, 5-ethyl-1,3,4-oxadiazole-2-base, 5-(4-fluoro-phenyl)-1,2,4-oxadiazole-3-base 5-sec.-propyl-isoxazole-3-base 5-(5-methyl-isoxazole-3-yl)-oxazoles-2-base 5-(5-methyl-thiophene-2-yl)-oxazoles-2-base oxazole-2-base, 3-phenyl-1,2,4-oxadiazole-5-base, 5-phenyl-1,2,4-oxadiazole-3-base, 5-thiophene-2-base-oxazoles-2-base, 5-(4-Trifluoromethoxyphen-l)-1,3,4-oxadiazole-2-base.
32. the compound of claim 31, wherein R 6Be benzoxazole-2-base, 3-cyclopropyl-1,2,4-oxadiazole-5-Ji, oxazole-2-base, 5-cyclopropyl-1,2,4-oxadiazole-3-base.
33. the compound of claim 17, wherein R 11Be-C (O) OR 13Or-S (O) 2R 13, R wherein 13Be alkyl or (C 6-12) aryl.
34. the compound of claim 28, wherein R 11Be-C (O) OC (CH 3) 3Or
35. the compound of claim 3 is selected from down the group compound:
Morpholine-4-formic acid (S)-1-[(S)-and 1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides;
Morpholine-4-formic acid (S)-1-[(S)-and 1-(5-cyclopropyl-1,3,4-oxadiazole-2-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides;
Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{ (S)-1-[5-(4-Trifluoromethoxyphen-l)-1,3,4-oxadiazole-2-carbonyl]-the propyl group formamyl }-hexyl)-acid amides;
Morpholine-4-formic acid (S)-1-[(S)-and 1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-two fluoro-4-phenyl-butyl }-acid amides;
Morpholine-4-formic acid 1-[1-(3-cyclopropyl-[1,2,4] oxadiazole-5-carbonyl)-propyl group formamyl] and-3,3-two fluoro-5-methyl-hexyls }-acid amides;
Morpholine-4-formic acid (S)-1-[(S)-and 1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-difluoro butyl }-acid amides;
Morpholine-4-formic acid (S)-3,3-two fluoro-1-[(S)-1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-butyl }-acid amides;
Morpholine-4-formic acid (S)-3,3-two fluoro-1-[(S)-1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl group formamyl]-butyl }-acid amides;
Morpholine-4-formic acid 1-[1-(5-cyclopropyl-[1,3,4] oxadiazole-2-carbonyl)-propyl group formamyl] and-3,3-two fluoro-4-phenyl-butyl }-acid amides;
Morpholine-4-formic acid 3,3-two fluoro-1-[1-(the different propyl group isoxazole of 5--3-carbonyl)-propyl group formamyl]-hexyl }-acid amides;
Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{1-[5-(5-methyl-isoxazole-3-yl)-oxazole-2-carbonyl]-the propyl group formamyl }-hexyl)-acid amides;
Morpholine-4-formic acid (S)-3,3-two fluoro-1-[(S)-1-(oxazole-2-carbonyl)-propyl group formamyl]-4-phenyl-butyl }-acid amides;
Morpholine-4-formic acid (S)-3,3-two fluoro-4-phenyl-1-[(S)-1-(5-thiophene-2-base oxazole-2-carbonyl)-propyl group formamyl]-butyl }-acid amides;
Morpholine-4-formic acid (S)-1-[(S)-and 1-(benzoxazole-2-carbonyl)-butyl formamyl]-3,3-two fluoro-4-phenyl-butyl }-acid amides;
Morpholine-4-formic acid [1-(2-benzoxazole-2-base-1-methoxymethyl-2-oxoethyl formamyl)-3,3-two fluoro-4-phenyl-butyl]-acid amides;
Morpholine-4-formic acid (S)-1-[(S)-and 1-(benzoxazole-2-carbonyl)-1-methyl-butyl formamyl]-3,3-two fluoro-4-phenyl-butyl }-acid amides;
Morpholine-4-formic acid [(S)-and 1-((S)-1-cyano group-3-phenyl propyl formamyl)-3,3-two fluoro-4-phenyl-butyl]-acid amides;
Morpholine-4-formic acid [(S)-and 1-(cyano methyl-formamyl)-3,3-two fluoro-4-phenyl-butyl]-acid amides;
Morpholine-4-formic acid [(S)-3,3-two fluoro-1-((S)-1-formyl radical-1-methyl-butyl formamyl)-4-phenyl-butyl]-acid amides;
Morpholine-4-formic acid (S)-and 1-[1-(5-ethyl-[1,3,4] oxadiazole-2-carbonyl)-propyl group formamyl]-3,3-two fluoro-4-phenyl-butyl }-acid amides;
Morpholine-4-formic acid (S)-and 1-[1-(the 5-tertiary butyl-[1,2,4] oxadiazole-3-carbonyl)-propyl group formamyl]-3,3-two fluoro-4-phenyl-butyl }-acid amides;
Morpholine-4-formic acid (S)-3,3-two fluoro-4-phenyl-1-[(S)-1-(5-phenyl-[1,2,4] oxadiazole-3-yl)-propyl group formamyl]-butyl }-acid amides;
[(S)-and 1-(cyano methyl-formamyl)-3,3-two fluoro-4-phenyl-butyl]-benzyl carbamate;
(S)-4,4-two fluoro-5-phenyl-2-(tetrahydrochysene-pyrans-4-base is amino)-valeric acid Cyanomethyl amides;
(S)-4,4-two fluoro-2-isobutylamino-5-phenylpentanoic acid Cyanomethyl amides;
Morpholine-4-formic acid [(S)-and 1-((S)-1-benzenesulfonyl-3-oxo-azepan-4-base formamyl)-3,3-two fluoro-4-phenyl-butyl]-acid amides;
(S)-and 4-{ (S)-4,4-two fluoro-2-[(morpholine-4-carbonyls)-amino]-5-phenyl pentanoyl amino }-3-oxo-azepan-1-t-butyl formate;
Morpholine-4-formic acid ((S)-1-{ (S)-1-[(5-ethyl-1,3,4-oxadiazole-2-yl)-hydroxymethyl]-the propyl group formamyl }-3,3-difluoro hexyl)-acid amides;
Morpholine-4-formic acid (S)-and 1-[1-(5-cyclopropyl-1,3,4-oxadiazole-2-carbonyl)-propyl group formamyl]-3,3-difluoro butyl }-acid amides;
Morpholine-4-formic acid (S)-and 1-[1-(5-cyclopropyl-1,2,4-oxadiazole-3-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides;
Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{ (S)-1-[5-(4-fluoro-phenyl)-1,2,4-oxadiazole-3-carbonyl]-the propyl group formamyl }-butyl)-acid amides;
Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{1-[5-(4-fluoro-phenyl)-1,2,4-oxadiazole-3-carbonyl]-the propyl group formamyl }-butyl)-acid amides;
Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{ (R)-1-[5-(4-fluoro-phenyl)-1,2,4-oxadiazole-3-carbonyl]-the propyl group formamyl }-butyl)-acid amides;
Morpholine-4-formic acid (S)-1-[(S)-1-(benzoxazole-2-carbonyl)-the propyl group formamyl]-3,3-difluoro butyl }-acid amides;
Morpholine-4-formic acid [(S)-and 1-(cyano methyl-formamyl)-3,3-difluoro hexyl]-acid amides;
Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{ (R)-1-[5-(5-thiotolene-2-yl)-oxazole-2-carbonyl]-the propyl group formamyl }-hexyl)-acid amides;
Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{ (S)-1-[5-(5-thiotolene-2-yl)-oxazole-2-carbonyl]-the propyl group formamyl }-hexyl)-acid amides;
And their corresponding N-oxide compounds, their prodrug, their protected derivative, their independent isomer and isomer mixture; And the pharmacy acceptable salt and the solvate (for example hydrate) of this class formula (Ia) compound and their N-oxide compound, their prodrug, their protected derivative, their independent isomer and isomer mixture.
36. contain the compound of claim 2 and the pharmaceutical composition of pharmaceutical acceptable excipient.
37. suppress the method for patient tissue proteolytic enzyme S, wherein the increase of cathepsin S enzymic activity promotes described patient's pathology illness, this method is to the compound of the claim 2 of described patient's administering therapeutic significant quantity.
38. the compound of claim 3 is used for the treatment of purposes in patient's the medicine in preparation, described patient suffers from or easily suffers from the illness that can improve by this compound of using as cathepsin S inhibitor.
39. the compound of claim 35 is used for the treatment of purposes in patient's the medicine in preparation, described patient suffers from or easily suffers from the illness that can improve by this compound of using as cathepsin S inhibitor.
40. the compound of claim 3 is used for the treatment of purposes in patient's the medicine in preparation, described patient suffers from or easily suffers from the illness that can improve by this compound of using as cathepsin B inhibitors.
41. the compound of claim 3 is used for the treatment of purposes in patient's the medicine in preparation, described patient suffers from or easily suffers from the illness that can improve by this compound of using as cathepsin K inhibitor.
42. following arbitrary compound and their corresponding N-oxide compounds, their prodrug, their protected derivative, their independent isomer and isomer mixture; And the pharmacy acceptable salt of this class formula (Ia) compound and their N-oxide compound and their prodrug, their protected derivative, their independent isomer and isomer mixture and solvate (for example hydrate) according to any one purposes in the claim 38 to 41, be used to prepare the medicine of inhibition of histone enzyme S, K or B enzymic activity:
Morpholine-4-formic acid (S)-1-[(S)-and 1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides,
Morpholine-4-formic acid (S)-1-[(S)-and 1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-two fluoro-4-phenyl-butyl }-acid amides,
Morpholine-4-formic acid (S)-1-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-difluoro butyl }-acid amides or
Morpholine-4-formic acid (S)-3,3-two fluoro-1-[(S)-1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-butyl }-acid amides.
43. the purposes of claim 42, be used for the treatment of pain, osteoarthritis, osteoporosis, or cancer such as lung cancer, leukemia (B-and T-cell, acute), ovarian cancer, sarcoma, Kaposi sarcoma, intestinal cancer, lymphoglandula cancer, brain tumor, mammary cancer, carcinoma of the pancreas, prostate cancer or skin carcinoma.
44. treatment suffers from the patient's who relates to disease that the cathepsin S level raises or medical conditions method, described disease or medical conditions are selected from sacroiliitis, atherosclerosis, wind-puff, osteoporosis, pain, muscular dystrophy, inflammation, multiple sclerosis, intestines and easily swash disease, rheumatoid arthritis, asthma, autoimmune reaction, chronic obstructive pulmonary disease, and bronchiolitis, this method comprises compound from the claim 3 of inhibition of histone enzyme S significant quantity to described patient that use.
45. treatment suffers from the patient's who relates to disease that cathepsin K or B level raise or medical conditions method, described disease or medical conditions are selected from osteoarthritis, osteoporosis or cancer, as lung cancer, leukemia (B-and T-cell, acute), ovarian cancer, sarcoma, Kaposi sarcoma, intestinal cancer, lymphoglandula cancer, brain tumor, mammary cancer, carcinoma of the pancreas, prostate cancer and skin carcinoma, this method comprises compound from the claim 3 of inhibition of histone enzyme K or B significant quantity to this patient that use.
46. treatment suffers from the patient's who relates to disease that the L-Cysteine HCL Anhydrous level raises or medical conditions method, described disease or medical conditions are selected from sacroiliitis, atherosclerosis, wind-puff, osteoporosis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, periodontopathy, the alochromacy leukodystrophy, the juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Ge Leifusishi disease, myasthenia gravis, systemic lupus erythematous, the intestines irritable, rheumatoid arthritis and struma lymphomatosa, asthma, autoimmune reaction, chronic obstructive pulmonary disease and bronchiolitis, this method comprise compound from the claim 3 that suppresses the L-Cysteine HCL Anhydrous significant quantity to described patient that use.
47. treatment suffers from the patient's who relates to disease that cathepsin K or B level raise or medical conditions method, described disease or medical conditions are selected from pain, osteoarthritis, osteoporosis or cancer, as lung cancer, leukemia (B-and T-cell, acute), ovarian cancer, sarcoma, Kaposi sarcoma, intestinal cancer, lymphoglandula cancer, brain tumor, mammary cancer, carcinoma of the pancreas, prostate cancer and skin carcinoma, this method comprises compound from the claim 35 of inhibition of histone enzyme K or B significant quantity to described patient that use.
48. treatment suffers from the patient's who relates to disease that the L-Cysteine HCL Anhydrous level raises or medical conditions method, described disease or medical conditions are selected from pain, osteoarthritis, osteoporosis or cancer, as lung cancer, leukemia (B-and T-cell, acute), ovarian cancer, sarcoma, Kaposi sarcoma, intestinal cancer, lymphoglandula cancer, brain tumor, mammary cancer, carcinoma of the pancreas, prostate cancer and skin carcinoma, this method comprises compound from the claim 42 that suppresses the L-Cysteine HCL Anhydrous significant quantity to described patient that use.
49. inhibition of histone enzyme K level rising patient's the active method of cathepsin K optionally, it comprises compound from the claim 3 of inhibition of histone enzyme K significant quantity to the patient that needs are arranged that use.
50. inhibition of histone enzyme K level rising patient's the active method of cathepsin K optionally, it comprises compound from the claim 42 of inhibition of histone enzyme K significant quantity to the patient that needs are arranged that use.
51. inhibition of histone enzyme S level rising patient's the active method of cathepsin S optionally, it comprises compound from the claim 3 of inhibition of histone enzyme S significant quantity to the patient that needs are arranged that use.
52. inhibition of histone enzyme S level rising patient's the active method of cathepsin S optionally, it comprises compound from the claim 35 of inhibition of histone enzyme S significant quantity to the patient that needs are arranged that use.
53. inhibition of histone enzyme B level rising patient's the active method of cathepsin B optionally, it comprises compound from the claim 3 of inhibition of histone enzyme B significant quantity to the patient that needs are arranged that use.
54. inhibition of histone enzyme B level rising patient's the active method of cathepsin B optionally, it comprises compound from the claim 42 of inhibition of histone enzyme B significant quantity to the patient that needs are arranged that use.
55. the arthritic method of treatment mammalian bone comprises the compound to the claim 42 of described administration significant quantity.
56. the compound of any one, wherein R in the claim 3 to 10,12 to 18 or 20 to 30 1Be
Figure A2004800389120015C1
57. the compound of claim 3 is selected from down group:
Perhydro-1,4-oxygen azepine -4-formic acid (S)-1-[(S)-and 1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-difluoro butyl }-acid amides;
Perhydro-1,4-oxygen azepine -4-formic acid (S)-1-[(S)-and 1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides;
Morpholine-4-formic acid (S)-1-[(S)-and 1-(3-sec.-propyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides;
Morpholine-4-formic acid (S)-1-[(S)-and 1-(the 5-tertiary butyl-1,2,4-oxadiazole-3-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides;
Morpholine-4-formic acid (S)-and 1-[1-(the 5-tertiary butyl-1,2,4-oxadiazole-3-carbonyl)-propyl group formamyl]-3,3-two fluoro-4-phenyl-butyl }-acid amides;
Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{ (S)-1-[5-(4-fluoro-phenyl)-1,2,4-oxadiazole-3-carbonyl]-the propyl group formamyl }-butyl)-acid amides;
Morpholine-4-formic acid (S)-and 1-[1-(5-cyclopropyl-1,2,4-oxadiazole-3-carbonyl)-propyl group formamyl]-3,3-two fluoro-4-phenyl-butyl }-acid amides;
Perhydro-1,4-oxygen azepine -4-formic acid (S)-and 1-[1-(5-cyclopropyl-1,2,4-oxadiazole-3-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides;
Perhydro-1,4-oxygen azepine -4-formic acid [(S)-and 1-(cyano methyl-formamyl)-3,3-difluoro hexyl]-acid amides;
Perhydro-1,4-oxygen azepine -4-formic acid [(S)-and 1-((S)-1-cyano group propyl group formamyl)-3,3-difluoro hexyl]-acid amides; And
Morpholine-4-formic acid [(S)-and 1-(1-cyano group-cyclopropyl formamyl)-3,3-difluoro hexyl]-acid amides.
58. following arbitrary compound according to any one purposes in the claim 41 to 42:
Perhydro-1,4-oxygen azepine -4-formic acid (S)-1-[(S)-and 1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-difluoro butyl }-acid amides;
Perhydro-1,4-oxygen azepine -4-formic acid (S)-1-[(S)-and 1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides;
Morpholine-4-formic acid (S)-1-[(S)-and 1-(3-sec.-propyl-1,2,4-oxadiazole-5-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides;
Morpholine-4-formic acid (S)-1-[(S)-and 1-(the 5-tertiary butyl-1,2,4-oxadiazole-3-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides;
Morpholine-4-formic acid (S)-and 1-[1-(the 5-tertiary butyl-1,2,4-oxadiazole-3-carbonyl)-propyl group formamyl]-3,3-two fluoro-4-phenyl-butyl }-acid amides;
Morpholine-4-formic acid ((S)-3,3-two fluoro-1-{ (S)-1-[5-(4-fluoro-phenyl)-1,2,4-oxadiazole-3-carbonyl]-the propyl group formamyl }-butyl)-acid amides;
Morpholine-4-formic acid (S)-and 1-[1-(5-cyclopropyl-1,2,4-oxadiazole-3-carbonyl)-propyl group formamyl]-3,3-two fluoro-4-phenyl-butyl }-acid amides;
Perhydro-1,4-oxygen azepine -4-formic acid (S)-and 1-[1-(5-cyclopropyl-1,2,4-oxadiazole-3-carbonyl)-propyl group formamyl]-3,3-difluoro hexyl }-acid amides;
Perhydro-1,4-oxygen azepine -4-formic acid [(S)-and 1-(cyano methyl-formamyl)-3,3-difluoro hexyl]-acid amides;
Perhydro-1,4-oxygen azepine -4-formic acid [(S)-and 1-((S)-1-cyano group propyl group formamyl)-3,3-difluoro hexyl]-acid amides; With
Morpholine-4-formic acid [(S)-and 1-(1-cyano group-cyclopropyl formamyl)-3,3-difluoro hexyl]-acid amides.
59. inhibition of histone enzyme K level rising patient's the active method of cathepsin K optionally, it comprises compound from the claim 55 of inhibition of histone enzyme K significant quantity to the patient that needs are arranged that use.
60. inhibition of histone enzyme S level rising patient's the active method of cathepsin S optionally, it comprises compound from the claim 55 of inhibition of histone enzyme S significant quantity to the patient that needs are arranged that use.
61. inhibition of histone enzyme B level rising patient's the active method of cathepsin B optionally, it comprises compound from the claim 55 of inhibition of histone enzyme B significant quantity to the patient that needs are arranged that use.
62. the arthritic method of treatment mammalian bone comprises the compound to the claim 55 of described administration significant quantity.
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